rs17226980

Positions:

• chr16-89758657-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000135.4(FANCA):​c.2901C>T​(p.Ser967=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 1,613,924 control chromosomes in the GnomAD database, including 5,773 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. S967S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.060 (424 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5349 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.330

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-89758657-G-A is Benign according to our data. Variant chr16-89758657-G-A is described in ClinVar as [Benign]. Clinvar id is 255251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.2901C>T	p.Ser967=	synonymous_variant	30/43	ENST00000389301.8
FANCA	NM_001286167.3	c.2901C>T	p.Ser967=	synonymous_variant	30/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.2901C>T	p.Ser967=	synonymous_variant	30/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9078 AN: 152154 Hom.: 423 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0671 AC: 16869 AN: 251436 Hom.: 1007 AF XY: 0.0662 AC XY: 8999 AN XY: 135904

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0582

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.0211

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0767

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0790 AC: 115510 AN: 1461652 Hom.: 5349 Cov.: 32 AF XY: 0.0775 AC XY: 56348 AN XY: 727136

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0569

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0865

Gnomad4 OTH exome AF: 0.0827

GnomAD4 genome AF: 0.0597 AC: 9085 AN: 152272 Hom.: 424 Cov.: 32 AF XY: 0.0578 AC XY: 4300 AN XY: 74450

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0373

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.0831

Gnomad4 OTH AF: 0.0563

Alfa AF: 0.0703 Hom.: 236

Bravo AF: 0.0574

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0744

EpiControl AF: 0.0730

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.28
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17226980; hg19: chr16-89825065; COSMIC: COSV59795612;