chr3-10046582-G-T

Position:

• chr3-10046582-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001018115.3(FANCD2):​c.1137G>T​(p.Val379Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (0 hom., cov: 44)
  • Exomes 𝑓: 0.19 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08

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]

FANCD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-10046582-G-T is Benign according to our data. Variant chr3-10046582-G-T is described in ClinVar as [Benign]. Clinvar id is 342260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10046582-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1137G>T	p.Val379Val	splice_region_variant, synonymous_variant	15/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1137G>T	p.Val379Val	splice_region_variant, synonymous_variant	15/44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 55909 AN: 125696 Hom.: 0 Cov.: 44 FAILED QC

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.435

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.185 AC: 138739 AN: 749832 Hom.: 0 Cov.: 42 AF XY: 0.191 AC XY: 71545 AN XY: 375272

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.0784

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.445 AC: 55942 AN: 125774 Hom.: 0 Cov.: 44 AF XY: 0.442 AC XY: 27101 AN XY: 61290

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.442

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.435

Alfa AF: 0.334 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.66
CADD	Benign	9.7
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs72492997; hg19: chr3-10088266; COSMIC: COSV55036171; COSMIC: COSV55036171;