rs17233497

Positions:

chr16-89748744-G-A

Variant summary

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

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 (★★).

Frequency

Genomes: 𝑓 0.052 ( 266 hom., cov: 33)

Exomes 𝑓: 0.074 ( 4572 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:11O:1

Conservation

PhyloP100: 2.43

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=0.004563749).

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	Protein	UniProt
FANCA	NM_000135.4 link	c.3263C>T	p.Ser1088Phe	missense_variant	33/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.3263C>T	p.Ser1088Phe	missense_variant	33/43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.3263C>T	p.Ser1088Phe	missense_variant	33/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0519

AC:

7902

AN:

152198

Hom.:

266

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0729

AC XY:

53008

AN XY:

726990

show subpopulations

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.:

AF XY:

0.0492

AC XY:

3664

AN XY:

74482

show subpopulations

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:

ESP6500EA

AF:

0.0810

AC:

697

ExAC

AF:

0.0500

AC:

6067

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0745

EpiControl

AF:

0.0728

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Fanconi anemia complementation group A

Pathogenic:1Benign: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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Benign

0.37

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

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

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