rs1800340

chr16-89771670-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):c.2151+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,336 control chromosomes in the GnomAD database, including 121,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14251 hom., cov: 31)
  • Exomes 𝑓: 0.37 (107601 hom.)
• Consequence: FANCA NM_000135.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001916
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-89771670-A-G is Benign according to our data. Variant chr16-89771670-A-G is described in ClinVar as [Benign]. Clinvar id is 255245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89771670-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.2151+8T>C		splice_region_variant, intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.2151+8T>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.2151+8T>C		splice_region_variant, intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62868 AN: 151740 Hom.: 14233 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.438 AC: 110023 AN: 251442 Hom.: 27519 AF XY: 0.431 AC XY: 58561 AN XY: 135894

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.365 AC: 533872 AN: 1461478 Hom.: 107601 Cov.: 39 AF XY: 0.369 AC XY: 268195 AN XY: 727066

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.618

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.817

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.414 AC: 62938 AN: 151858 Hom.: 14251 Cov.: 31 AF XY: 0.428 AC XY: 31765 AN XY: 74214

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.753

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.374

Alfa AF: 0.355 Hom.: 6358

Bravo AF: 0.425

Asia WGS AF: 0.654 AC: 2273 AN: 3478

EpiCase AF: 0.306

EpiControl AF: 0.294

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.017
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs1800340; hg19: chr16-89838078; COSMIC: COSV66881670; COSMIC: COSV66881670;