VCV000446520.19 - ClinVar

NM_057175.4(NAA15):c.228_232del (p.Asp76Glufs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_057175.4(NAA15):c.228_232del (p.Asp76Glufs)

Variation ID: 446520 Accession: VCV000446520.19

Type and length

Deletion, 5 bp

Location

Cytogenetic: 4q31.1 4: 139336933-139336937 (GRCh38) [ NCBI UCSC ] 4: 140258087-140258091 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 9, 2017	Oct 26, 2024	Nov 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_057175.5:c.228_232del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_476516.1:p.Asp76fs	frameshift
NM_057175.3:c.228_232del
NM_057175.3:c.228_232delCTTGA
NC_000004.12:g.139336936_139336940del
NC_000004.11:g.140258090_140258094del
NG_053037.1:g.40470_40474del

... more HGVS ... less HGVS

Protein change

D76fs

Other names

DEL/INS, NT225

Canonical SPDI

NC_000004.12:139336932:TGACTTGA:TGA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA555034937 OMIM: 608000.0003 dbSNP: rs1380822792 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NAA15		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	407	452

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Intellectual disability, autosomal dominant 50	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 8, 2022	RCV000515798.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 9, 2023	RCV000793395.15

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability, autosomal dominant 50 Affected status: yes Allele origin: maternal	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI-WGS-HudsonAlpha Accession: SCV000803186.1 First in ClinVar: Dec 09, 2017 Last updated: Dec 09, 2017	Number of individuals with the variant: 1 Clinical Features: Stereotypy (present) , Sleep disturbance (present) , Self-biting (present) , Skin-picking (present) , Developmental regression (present) , Feeding difficulties (present)
Pathogenic (Jun 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 50 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568192.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PVS1, PS2, PM2
Pathogenic (Mar 11, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000932744.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28191889‚ 29656860 Comment: Loss-of-function variants in NAA15 are known to be pathogenic (PMID: 28191889, 29656860). For these reasons, this variant has been classified as Pathogenic. This variant has … (more) Loss-of-function variants in NAA15 are known to be pathogenic (PMID: 28191889, 29656860). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in an individual affected with autism spectrum disorder (PMID:¬†28191889). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp76Glufs*20) in the NAA15 gene. It is expected to result in an absent or disrupted protein product. (less)
Pathogenic (Nov 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001983272.4 First in ClinVar: Oct 30, 2021 Last updated: Oct 08, 2024	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28191889, 33004838, 35710456, 29656860) (less)
Pathogenic (Jul 07, 2021)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 50, WITH BEHAVIORAL ABNORMALITIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV000611895.2 First in ClinVar: Dec 09, 2017 Last updated: Jul 10, 2021	Publications: PubMed (1) PubMed: 28191889 Comment on evidence: In a male patient (patient 11, AGRE_03C14733) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787) manifest as autism spectrum disorder, Stessman et … (more) In a male patient (patient 11, AGRE_03C14733) with autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50; 617787) manifest as autism spectrum disorder, Stessman et al. (2017) identified a de novo heterozygous del/ins mutation (c.225_230delTGACTTinsT, NM_057175.3) in the NAA15 gene, resulting in a frameshift and premature termination (Asp76GlufsTer20). (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV002522461.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Intellectual disability, autosomal dominant 50 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005200055.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

Loss-of-function variants in NAA15 are known to be pathogenic (PMID: 28191889, 29656860). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in an individual affected with autism spectrum disorder (PMID:¬†28191889). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp76Glufs*20) in the NAA15 gene. It is expected to result in an absent or disrupted protein product.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28191889, 33004838, 35710456, 29656860)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.	Cheng H	American journal of human genetics	2018	PMID: 29656860
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.	Stessman HA	Nature genetics	2017	PMID: 28191889

Text-mined citations for rs1380822792 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_057175.4(NAA15):c.228_232del (p.Asp76Glufs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1380822792 ...