rs17232246

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000389301.8(FANCA):c.542C>T(p.Ala181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,613,960 control chromosomes in the GnomAD database, including 1,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A181E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.046 ( 576 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 532 hom. )

Consequence

FANCA
ENST00000389301.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8O:1

Conservation

PhyloP100: 1.00

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019883811).

BP6

Variant 16-89808348-G-A is Benign according to our data. Variant chr16-89808348-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FANCA	NM_000135.4 linkuse as main transcript	c.542C>T	p.Ala181Val	missense_variant	6/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 linkuse as main transcript	c.542C>T	p.Ala181Val	missense_variant	6/43		NP_001273096.1
FANCA	NM_001018112.3 linkuse as main transcript	c.542C>T	p.Ala181Val	missense_variant	6/11		NP_001018122.1
FANCA	NM_001351830.2 linkuse as main transcript	c.446C>T	p.Ala149Val	missense_variant	5/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.542C>T	p.Ala181Val	missense_variant	6/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0459

AC:

6977

AN:

152004

Hom.:

574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0122

AC:

3069

AN:

251326

Hom.:

243

AF XY:

0.00849

AC XY:

1153

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.00741

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00474

AC:

6928

AN:

1461838

Hom.:

532

Cov.:

AF XY:

0.00401

AC XY:

2916

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.00809

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.0459

AC:

6986

AN:

152122

Hom.:

576

Cov.:

AF XY:

0.0442

AC XY:

3284

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.160

Gnomad4 AMR

AF:

0.0151

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.00813

Hom.:

206

Bravo

AF:

0.0522

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.168

AC:

738

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0153

AC:

1853

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 30, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.16

T;.;.;T;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.77

T;T;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L;.;.;.

MutationTaster

Benign

0.57

N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;N;D;D;D;D

REVEL

Benign

0.17

Sift

Benign

0.25

T;T;T;T;T;T

Sift4G

Uncertain

0.047

D;D;T;T;T;T

Polyphen

0.91

P;.;B;.;B;B

Vest4

0.20

ClinPred

0.0095

GERP RS

2.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.025

gMVP

0.064

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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