NM_001113378.2(FANCI):c.3946G>A (p.Gly1316Arg) AND Fanconi anemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 8, 2022
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:: RCV000476737.7

Allele description [Variation Report for NM_001113378.2(FANCI):c.3946G>A (p.Gly1316Arg)]

NM_001113378.2(FANCI):c.3946G>A (p.Gly1316Arg)

Genes:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
FANCI:FA complementation group I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_001113378.2(FANCI):c.3946G>A (p.Gly1316Arg)

HGVS:

NC_000015.10:g.89316418G>A
NG_008218.2:g.23378C>T
NG_011736.1:g.77456G>A
NM_001113378.2:c.3946G>AMANE SELECT
NM_001126131.2:c.*333C>T
NM_001376910.1:c.3667G>A
NM_001376911.1:c.3946G>A
NM_002693.3:c.*333C>TMANE SELECT
NM_018193.3:c.3766G>A
NP_001106849.1:p.Gly1316Arg
NP_001106849.1:p.Gly1316Arg
NP_001363839.1:p.Gly1223Arg
NP_001363840.1:p.Gly1316Arg
NP_060663.2:p.Gly1256Arg
LRG_500t1:c.3946G>A
LRG_765t1:c.*333C>T
LRG_500:g.77456G>A
LRG_500p1:p.Gly1316Arg
LRG_765:g.23378C>T
NC_000015.9:g.89859649G>A
NM_001113378.1:c.3946G>A
NM_002693.2:c.*333C>T

Protein change:

G1223R

Links:

dbSNP: rs369058619

NCBI 1000 Genomes Browser:

rs369058619

Molecular consequence:

NM_001126131.2:c.*333C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_002693.3:c.*333C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001113378.2:c.3946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376910.1:c.3667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376911.1:c.3946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_018193.3:c.3766G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000547812	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 8, 2022)	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

SCV000547812

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 8, 2022)

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, SCV000547812.4

#	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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1316 of the FANCI protein (p.Gly1316Arg). This variant is present in population databases (rs369058619, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FANCI-related conditions. This missense change has been observed to co-occur in individuals with a different variant in FANCI that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 408231). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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