NM_000135.4(FANCA):c.4186A>G (p.Ile1396Val) AND Fanconi anemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 17, 2021
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:: RCV001999351.5

Allele description [Variation Report for NM_000135.4(FANCA):c.4186A>G (p.Ile1396Val)]

NM_000135.4(FANCA):c.4186A>G (p.Ile1396Val)

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.4186A>G (p.Ile1396Val)

HGVS:

NC_000016.10:g.89738956T>C
NG_011706.1:g.82702A>G
NM_000135.4:c.4186A>GMANE SELECT
NM_001113525.2:c.*710T>CMANE SELECT
NM_001286167.3:c.4190A>G
NM_152287.4:c.*710T>C
NP_000126.2:p.Ile1396Val
NP_000126.2:p.Ile1396Val
NP_001273096.1:p.Asp1397Gly
LRG_495t1:c.4186A>G
LRG_495:g.82702A>G
LRG_495p1:p.Ile1396Val
NC_000016.9:g.89805364T>C
NM_000135.2:c.4186A>G
NR_110122.2:n.2710T>C
NR_110126.2:n.2593T>C
NR_110128.2:n.2533T>C
NR_110129.2:n.2627T>C

Protein change:

D1397G

Links:

dbSNP: rs1376923890

NCBI 1000 Genomes Browser:

rs1376923890

Molecular consequence:

NM_001113525.2:c.*710T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*710T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000135.4:c.4186A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286167.3:c.4190A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_110122.2:n.2710T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2593T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2533T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2627T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV002278226	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002278226

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 17, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002278226.2

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

Description

This sequence change replaces isoleucine with valine at codon 1396 of the FANCA protein (p.Ile1396Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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