rs1800358

chr16-89742911-T-Cchr16-89742911-T-G

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.3654A>G(p.Pro1218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,748 control chromosomes in the GnomAD database, including 9,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1498 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7855 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.82

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=-0.91).
• BP6: Variant 16-89742911-T-C is Benign according to our data. Variant chr16-89742911-T-C is described in ClinVar as [Benign]. Clinvar id is 255261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.82 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.3654A>G	p.Pro1218=	synonymous_variant	37/43	ENST00000389301.8
FANCA	NM_001286167.3	c.3654A>G	p.Pro1218=	synonymous_variant	37/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.3654A>G	p.Pro1218=	synonymous_variant	37/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19285 AN: 152034 Hom.: 1494 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0634

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0849

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.101 AC: 25429 AN: 251310 Hom.: 1761 AF XY: 0.0999 AC XY: 13577 AN XY: 135856

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0819

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.0841

Gnomad NFE exome AF: 0.0882

Gnomad OTH exome AF: 0.0822

GnomAD4 exome AF: 0.0982 AC: 143511 AN: 1461596 Hom.: 7855 Cov.: 32 AF XY: 0.0982 AC XY: 71378 AN XY: 727124

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0386

Gnomad4 ASJ exome AF: 0.0810

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0806

Gnomad4 NFE exome AF: 0.0947

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.127 AC: 19312 AN: 152152 Hom.: 1498 Cov.: 32 AF XY: 0.124 AC XY: 9249 AN XY: 74398

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.0632

Gnomad4 ASJ AF: 0.0857

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.0849

Gnomad4 NFE AF: 0.0943

Gnomad4 OTH AF: 0.107

Alfa AF: 0.103 Hom.: 497

Bravo AF: 0.128

Asia WGS AF: 0.177 AC: 614 AN: 3478

EpiCase AF: 0.0899

EpiControl AF: 0.0879

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

not specified Benign:2

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	-	- -

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	-0.91
Cadd	Benign	0.016
Dann	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1800358; hg19: chr16-89809319; COSMIC: COSV57066232; COSMIC: COSV57066232;