rs17233141

chr16-89767168-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S858T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (128 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 U:1 B:14 O:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.2574C>G	p.Ser858Arg	missense_variant	27/43	ENST00000389301.8
FANCA	NM_001286167.3	c.2574C>G	p.Ser858Arg	missense_variant	27/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.2574C>G	p.Ser858Arg	missense_variant	27/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 978 AN: 152232 Hom.: 8 Cov.: 33

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.: 34 AF XY: 0.0117 AC XY: 1592 AN XY: 135898

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.: 30 AF XY: 0.00995 AC XY: 7234 AN XY: 726846

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.: 7 Cov.: 33 AF XY: 0.00646 AC XY: 481 AN XY: 74494

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.: 2

Bravo AF: 0.00565

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.0103 AC: 1250

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Uncertain:1 Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:2 Uncertain:1 Benign:2

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. -
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. -
Pathogenic, flagged submission	research	McDonnell Genome Institute, Washington University in St. Louis	Oct 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, 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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FANCA: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:4 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

FANCA-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs17233141; hg19: chr16-89833576; COSMIC: COSV59796377; COSMIC: COSV59796377;