rs17233497

Variant names:

• chr16-89748744-G-A
• rs17233497
• NM_000135.4:c.3263C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-89748744-G-A
• chr16-89748744-G-C
• chr16-89748744-G-T

Variant summary

Our verdict is Benign. The variant received -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. 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:11 O:1
• Conservation: PhyloP100: 2.43
• Publications: 48 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 24 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 VariationId is 134264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.3263C>T	p.Ser1088Phe	missense_variant	Exon 33 of 43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.3263C>T	p.Ser1088Phe	missense_variant	Exon 33 of 43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.3263C>T	p.Ser1088Phe	missense_variant	Exon 33 of 43	1	NM_000135.4	ENSP00000373952.3

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

GnomAD2 exomes AF: 0.0505 AC: 12675 AN: 250776 AF XY: 0.0511

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 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

African (AFR) AF: 0.0105 AC: 352 AN: 33480

American (AMR) AF: 0.0206 AC: 920 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 1491 AN: 26134

East Asian (EAS) AF: 0.0189 AC: 751 AN: 39698

South Asian (SAS) AF: 0.0192 AC: 1654 AN: 86250

European-Finnish (FIN) AF: 0.0579 AC: 3084 AN: 53276

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.0865 AC: 96134 AN: 1111654

Other (OTH) AF: 0.0665 AC: 4012 AN: 60374

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

African (AFR) AF: 0.0128 AC: 533 AN: 41580

American (AMR) AF: 0.0334 AC: 511 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5180

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4828

European-Finnish (FIN) AF: 0.0612 AC: 650 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0832 AC: 5657 AN: 68024

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0677 Hom.: 1201

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A Pathogenic:1 Benign:3

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: flagged submission

Collection Method: curation

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

Fanconi anemia Benign:2

Feb 06, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Prostate cancer Uncertain:1

Jul 01, 2015

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

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
PhyloP100		2.4
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17233497; hg19: chr16-89815152; COSMIC: COSV59796184; COSMIC: COSV59796184;