rs7647987

Positions:

• chr3-10099012-A-G

Variant summary

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

The NM_001018115.3(FANCD2):​c.4281+197A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,612,436 control chromosomes in the GnomAD database, including 29,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5952 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23963 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.424

Genes affected

FANCD2 (HGNC:3585): (FA complementation group D2) 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 D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-10099012-A-G is Benign according to our data. Variant chr3-10099012-A-G is described in ClinVar as [Benign]. Clinvar id is 342383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.4281+197A>G		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.4281+197A>G		intron_variant			NM_001018115.3	ENSP00000502379	P2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36737 AN: 151828 Hom.: 5944 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0899

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.173 AC: 252548 AN: 1460492 Hom.: 23963 Cov.: 33 AF XY: 0.173 AC XY: 125534 AN XY: 726614

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0759

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.242 AC: 36774 AN: 151944 Hom.: 5952 Cov.: 32 AF XY: 0.236 AC XY: 17561 AN XY: 74260

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0898

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.206

Alfa AF: 0.172 Hom.: 3675

Bravo AF: 0.258

Asia WGS AF: 0.146 AC: 511 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia complementation group D2 Benign:1

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. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.57

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: rs7647987; hg19: chr3-10140696; COSMIC: COSV55047463; COSMIC: COSV55047463;