chr16-89749788-T-C

Position:

chr16-89749788-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000135.4(FANCA):c.3181A>G(p.Ser1061Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -1.38

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA links:

FANCA (HGNC:):

FANCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06401548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.3181A>G	p.Ser1061Gly	missense_variant	32/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 linkuse as main transcript	c.3181A>G	p.Ser1061Gly	missense_variant	32/43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3181A>G	p.Ser1061Gly	missense_variant	32/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251340

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1061 of the FANCA protein (p.Ser1061Gly). This variant is present in population databases (rs369878171, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 408187). 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 with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 07, 2021	- -

Fanconi anemia complementation group A

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 24, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 26, 2019

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 25, 2022

The frequency of this variant in the general population, 0.000008 (2/251340 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with adenocarcinoma and small cell lung cancer (PMID: 32107087 (2020)). Additionally, the variant was reported to co-occur with two other pathogenic FANCA variants, in a patient with refractory leukocytopenia and thrombocytopenia (PMID: 31030435 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.038

DANN

Benign

0.39

DEOGEN2

Benign

0.097

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.55

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.16

Sift

Benign

0.64

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0020

B;.

Vest4

0.043

MutPred

0.22

Loss of glycosylation at S1061 (P = 0.0901);Loss of glycosylation at S1061 (P = 0.0901);

MVP

0.65

ClinPred

0.86

GERP RS

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.086

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over