rs17233497

chr16-89748744-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):c.3263C>T(p.Ser1088Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0721 in 1,613,668 control chromosomes in the GnomAD database, including 4,838 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1088S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.052 (266 hom., cov: 33)
  • Exomes 𝑓: 0.074 (4572 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:10 O:1
• Conservation: PhyloP100: 2.43

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.004563749).
• BP6: Variant 16-89748744-G-A is Benign according to our data. Variant chr16-89748744-G-A is described in ClinVar as [Benign]. Clinvar id is 134264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89748744-G-A is described in Lovd as [Benign]. Variant chr16-89748744-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.3263C>T	p.Ser1088Phe	missense_variant	33/43	ENST00000389301.8
FANCA	NM_001286167.3	c.3263C>T	p.Ser1088Phe	missense_variant	33/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.3263C>T	p.Ser1088Phe	missense_variant	33/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7902 AN: 152198 Hom.: 266 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0505 AC: 12675 AN: 250776 Hom.: 459 AF XY: 0.0511 AC XY: 6928 AN XY: 135616

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0236

Gnomad SAS exome AF: 0.0183

Gnomad FIN exome AF: 0.0590

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0742 AC: 108472 AN: 1461352 Hom.: 4572 Cov.: 32 AF XY: 0.0729 AC XY: 53008 AN XY: 726990

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.0206

Gnomad4 ASJ exome AF: 0.0571

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0579

Gnomad4 NFE exome AF: 0.0865

Gnomad4 OTH exome AF: 0.0665

GnomAD4 genome AF: 0.0519 AC: 7904 AN: 152316 Hom.: 266 Cov.: 33 AF XY: 0.0492 AC XY: 3664 AN XY: 74482

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.0264

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.0832

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0720 Hom.: 921

Bravo AF: 0.0484

TwinsUK AF: 0.0979 AC: 363

ALSPAC AF: 0.0817 AC: 315

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.0810 AC: 697

ExAC AF: 0.0500 AC: 6067

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.0745

EpiControl AF: 0.0728

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2021	Variant summary: FANCA c.3263C>T (p.Ser1088Phe) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.051 in 250776 control chromosomes in the gnomAD database, including 459 homozygotes. The observed variant frequency is approximately 23.34 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 benign. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Fanconi anemia complementation group A Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 23, 2019	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -

Malignant tumor of prostate Uncertain:1

Uncertain significance, flagged submission

research

Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine

Jul 01, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2019

This variant is associated with the following publications: (PMID: 31586946, 28864460, 10094191, 27153395, 27884173, 24728327, 20981092, 22995991) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.077	T;T
Polyphen		0.93	P;.
Vest4		0.15
ClinPred		0.032	T
GERP RS		3.7
Varity_R		0.17
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17233497; hg19: chr16-89815152; COSMIC: COSV59796184; COSMIC: COSV59796184;