NM_000135.4(FANCA):c.4168-2A>G AND Fanconi anemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001071425.6

Allele description [Variation Report for NM_000135.4(FANCA):c.4168-2A>G]

NM_000135.4(FANCA):c.4168-2A>G

Genes:

FANCA:FA complementation group A [Gene - OMIM - HGNC]
ZNF276:zinc finger protein 276 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000135.4(FANCA):c.4168-2A>G

HGVS:

NC_000016.10:g.89738976T>C
NG_011706.1:g.82682A>G
NM_000135.4:c.4168-2A>GMANE SELECT
NM_001113525.2:c.*730T>CMANE SELECT
NM_001286167.3:c.4172-2A>G
NM_152287.4:c.*730T>C
LRG_495t1:c.4168-2A>G
LRG_495:g.82682A>G
NC_000016.9:g.89805384T>C
NM_000135.2:c.4168-2A>G
NR_110122.2:n.2730T>C
NR_110126.2:n.2613T>C
NR_110128.2:n.2553T>C
NR_110129.2:n.2647T>C

Links:

dbSNP: rs1220672299

NCBI 1000 Genomes Browser:

rs1220672299

Molecular consequence:

NM_001113525.2:c.*730T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*730T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NR_110122.2:n.2730T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2613T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2553T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2647T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000135.4:c.4168-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001286167.3:c.4172-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Fanconi anemia (FA)
Synonyms:: Fanconi pancytopenia; Fanconi's anemia
Identifiers:: MONDO: MONDO:0019391; MeSH: D005199; MedGen: C0015625; Orphanet: 84; OMIM: PS227650

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Chain A [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
Chain A [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1
gi|157835868|pdb|2Q8G|A

Protein
"131860-97-4"[CompleteSynonym] (1)
PubChem Compound

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001236731	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17924555, 29098742, 10090479, 28102861, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001236731

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic subtyping of Fanconi anemia by comprehensive mutation screening.

Ameziane N, Errami A, Léveillé F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H.

Hum Mutat. 2008 Jan;29(1):159-66.

PubMed [citation]

PMID:: 17924555

A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families.

Kimble DC, Lach FP, Gregg SQ, Donovan FX, Flynn EK, Kamat A, Young A, Vemulapalli M, Thomas JW, Mullikin JC, Auerbach AD, Smogorzewska A, Chandrasekharappa SC.

Hum Mutat. 2018 Feb;39(2):237-254. doi: 10.1002/humu.23366. Epub 2017 Nov 22.

PubMed [citation]

PMID:: 29098742
PMCID:: PMC5762269

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001236731.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FANCA protein in which other variant(s) (p.Arg1400His) have been determined to be pathogenic (PMID: 17924555, 29098742; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 42, but is expected to preserve the integrity of the reading-frame (PMID: 10090479). ClinVar contains an entry for this variant (Variation ID: 864280). Disruption of this splice site has been observed in individuals with Fanconi anemia (PMID: 10090479, 28102861). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 41 of the FANCA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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