rs17233141

Positions:

chr16-89767168-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000135.4(FANCA):c.2574C>G(p.Ser858Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 1,613,284 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0092 ( 128 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2U:1B:15O:1

Conservation

PhyloP100: 1.79

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=0.008692145).

BP6

Variant 16-89767168-G-C is Benign according to our data. Variant chr16-89767168-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89767168-G-C is described in Lovd as [Likely_benign]. Variant chr16-89767168-G-C is described in Lovd as [Pathogenic]. Variant chr16-89767168-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0064 (975/152350) while in subpopulation SAS AF= 0.0255 (123/4826). AF 95% confidence interval is 0.0218. There are 7 homozygotes in gnomad4. There are 481 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.2574C>G	p.Ser858Arg	missense_variant	27/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.2574C>G	p.Ser858Arg	missense_variant	27/43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.2574C>G	p.Ser858Arg	missense_variant	27/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

978

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.0100

AC:

2527

AN:

251444

Hom.:

AF XY:

0.0117

AC XY:

1592

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0318

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.00871

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00922

AC:

13475

AN:

1460934

Hom.:

128

Cov.:

AF XY:

0.00995

AC XY:

7234

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00429

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0324

Gnomad4 FIN exome

AF:

0.00929

Gnomad4 NFE exome

AF:

0.00802

Gnomad4 OTH exome

AF:

0.00998

GnomAD4 genome

AF:

0.00640

AC:

975

AN:

152350

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

481

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0255

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.00794

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00831

Hom.:

Bravo

AF:

0.00565

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.0103

AC:

1250

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00927

EpiControl

AF:

0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Uncertain:1Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	This variant is associated with the following publications: (PMID: 24728327, 11091222, 30249500, 21279724, 24082139, 10094191, 27884173, 27153395, 26740942, 15591268, 23021409, 27148581, 30553997, 26799702, 26119737, 29084058, 25231023, 12955722) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FANCA: BP4, BS1, BS2 -

Fanconi anemia complementation group A

Pathogenic:2Uncertain:1Benign:2

Pathogenic, flagged submission	research	McDonnell Genome Institute, Washington University in St. Louis	Oct 22, 2015	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, flagged submission	clinical testing	Natera, Inc.	Jan 09, 2020	- -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: FANCA c.2574C>G (p.Ser858Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 251444 control chromosomes, predominantly at a frequency of 0.032 within the South Asian subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3), benign (n=4) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

FANCA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

9.9

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.13

Sift

Benign

0.063

T;T

Sift4G

Benign

0.072

T;T

Polyphen

0.26

B;.

Vest4

0.34

MutPred

0.25

Gain of MoRF binding (P = 0.054);Gain of MoRF binding (P = 0.054);

ClinPred

0.0082

GERP RS

1.6

Varity_R

0.069

gMVP

0.17

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