NM_000135.4(FANCA):c.4011-3_4011-2del AND Fanconi anemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 31, 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:: RCV003635958.1

Allele description [Variation Report for NM_000135.4(FANCA):c.4011-3_4011-2del]

NM_000135.4(FANCA):c.4011-3_4011-2del

Genes:

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

Variant type:

Deletion

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000135.4(FANCA):c.4011-3_4011-2del

HGVS:

NC_000016.10:g.89739291_89739292del
NG_011706.1:g.82366_82367del
NM_000135.4:c.4011-3_4011-2delMANE SELECT
NM_001113525.2:c.*1045_*1046delMANE SELECT
NM_001286167.3:c.4011-3_4011-2del
NM_152287.4:c.*1045_*1046del
LRG_495:g.82366_82367del
NC_000016.9:g.89805699_89805700del
NM_000135.4:c.4011-3_4011-2delTAMANE SELECT
NR_110122.2:n.3045_3046del
NR_110126.2:n.2928_2929del
NR_110128.2:n.2868_2869del
NR_110129.2:n.2962_2963del

Links:

dbSNP: rs911481295

NCBI 1000 Genomes Browser:

rs911481295

Molecular consequence:

NM_001113525.2:c.*1045_*1046del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*1045_*1046del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NR_110122.2:n.3045_3046del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2928_2929del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2868_2869del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2962_2963del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000135.4:c.4011-3_4011-2del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001286167.3:c.4011-3_4011-2del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004552107	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 34308366, 16199547, 19367192, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004552107

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 31, 2023)

germline

clinical testing

PubMed (4)
[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

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

Fiala EM, Jayakumaran G, Mauguen A, Kennedy JA, Bouvier N, Kemel Y, Fleischut MH, Maio A, Salo-Mullen EE, Sheehan M, Arnold AG, Latham A, Carlo MI, Cadoo K, Murkherjee S, Slotkin EK, Trippett T, Glade Bender J, Meyers PA, Wexler L, Dela Cruz FS, Cheung NK, et al.

Nat Cancer. 2021 Mar;2:357-365. doi: 10.1038/s43018-021-00172-1. Epub 2021 Feb 15.

PubMed [citation]

PMID:: 34308366
PMCID:: PMC8294573

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004552107.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 995895). Disruption of this splice site has been observed in individual(s) with neuroblastoma (PMID: 34308366). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects a splice site in intron 40 of the FANCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192).

#	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: Feb 28, 2024

ClinVar

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