chr16-89746848-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000135.4(FANCA):c.3391A>G(p.Thr1131Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000127 in 1,563,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 3.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

PP5

Variant 16-89746848-T-C is Pathogenic according to our data. Variant chr16-89746848-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89746848-T-C is described in Lovd as [Pathogenic]. Variant chr16-89746848-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3391A>G	p.Thr1131Ala	missense_variant	Exon 34 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.3391A>G	p.Thr1131Ala	missense_variant	Exon 34 of 43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.3391A>G	p.Thr1131Ala	missense_variant	Exon 34 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000868

AC:

AN:

172798

Hom.:

AF XY:

0.0000874

AC XY:

AN XY:

91560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000757

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000123

Gnomad NFE exome

AF:

0.000157

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

187

AN:

1411094

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

697304

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.000160

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000398

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:7

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Sue Richards. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000135.2(FANCA):c.3391A>G(T1131A) is a missense variant classified as pathogenic in the context of Fanconi anemia complementation group A. T1131A has been observed in cases with relevant disease (PMID: 22778927, 19367192, 15643609, 19278965, 19367192). Functional assessments of this variant are available in the literature (PMID: 12444097). T1131A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000135.2(FANCA):c.3391A>G(T1131A) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jun 12, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:6

Jun 16, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00014 (12/85380 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Fanconi anemia (FA) (PMIDs: 31192125 (2019), 29098742 (2018), 27577878 (2017), 22778927 (2012), 19367192 (2009), 17924555 (2008), 15643609 (2005)) and has been described affected individuals in the homozygous state as well as in trans with another pathogenic FANCA variant. One functional study suggests that this variant has similar properties as the wild-type in regards to phosphorylation and interaction with FANCC, but additional functional studies are needed to conclude this variant’s overall impact on gene and gene product (PMID: 12444097 (2002)). 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 damaging. Based on the available information, this variant is classified as pathogenic. -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCA: PM3:Strong, PM2 -

May 06, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.3391A>G, in exon 34 that results in an amino acid change, p.Thr1131Ala. This sequence change has been previously described in several patients with a clinical diagnosis of Fanconi anemia (PMIDs: 19278965, 9371798, 15643609); in some patients in a biallelic state with multi-exonic deletions (PMIDs: 17924555, 19367192) and in one patient in a homozygous state (PMID: 22778927). Some experimental studies showed that the mutant protein behaved similar to wild type-FANCA with respect to its interaction with FANCC, phosphorylation and localization to the nuclei (PMID: 12444097); however, authors proposed that further studies analyzing its mRNA and protein expression are required. The p.Thr1131Ala change affects a highly conserved amino acid residue located in a domain of the FANCA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr1131Ala substitution. This sequence change has been described in the gnomAD database with a low population frequency of 0.0083% (dbSNP rs574034197). These collective evidences indicate that this sequence change is likely pathogenic. -

Feb 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the p.(T1131A) variant significantly decreases FANCD2 monoubiquitination (PMID: 28864460); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 1792455, 27577878, 12444097, 9371798, 19367192, 15643609, 17924555, 26556299, 35417938, 36493725, 36744932, 37865086, 36139606, 31192125, 33332384, 29641532, 22778927, 29098742, 28864460, 39037077, 37688579) -

Jul 26, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM1, PM2, -

Aug 03, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia

Pathogenic:2

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1131 of the FANCA protein (p.Thr1131Ala). This variant is present in population databases (rs574034197, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 1792455, 1927896, 9371798, 12444097, 15643609, 19367192, 22778927). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 237048). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FANCA protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect FANCA function (PMID: 12444097). For these reasons, this variant has been classified as Pathogenic. -

Nov 05, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.69

T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;.

Vest4

0.83

MVP

0.96

ClinPred

0.41

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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