16-89746857-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000135.4(FANCA):c.3382C>G(p.Gln1128Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000448 in 1,562,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 1.69

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24859214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3382C>G	p.Gln1128Glu	missense_variant	Exon 34 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.3382C>G	p.Gln1128Glu	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.3382C>G	p.Gln1128Glu	missense_variant	Exon 34 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000355

AC:

AN:

1410264

Hom.:

Cov.:

AF XY:

0.00000431

AC XY:

AN XY:

696772

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000277

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:1Uncertain:1

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000135.2(FANCA):c.3382C>G(Q1128E) is a missense variant classified as a variant of uncertain significance in the context of Fanconi anemia complementation group A. Q1128E has been observed in cases with relevant disease (PMID: 9371798). Functional assessments of this variant are available in the literature (PMID: 30057198, 12444097, 16946016). Q1128E has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000135.2(FANCA):c.3382C>G(Q1128E) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Fanconi anemia

Uncertain:2

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1128 of the FANCA protein (p.Gln1128Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 9371798). ClinVar contains an entry for this variant (Variation ID: 551847). 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 affects FANCA function (PMID: 16946016, 30057198). 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. -

Jan 20, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.56

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.13

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0

B;.

Vest4

0.19

MutPred

0.70

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.93

ClinPred

0.079

GERP RS

4.1

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.036

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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