rs72492997

Variant names:

• chr3-10046582-G-T
• rs72492997
• NM_001018115.3:c.1137G>T

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 1.08
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group D2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 342260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1137G>T	p.Val379Val	splice_region_variant, synonymous_variant	Exon 15 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.445 AC: 55909 AN: 125696 Hom.: 0 Cov.: 44

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

GnomAD2 exomes AF: 0.138 AC: 20677 AN: 150050 AF XY: 0.135

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.0694

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.0898

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.248 AC: 4075 AN: 16428

American (AMR) AF: 0.154 AC: 3974 AN: 25828

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 3745 AN: 14362

East Asian (EAS) AF: 0.234 AC: 5794 AN: 24776

South Asian (SAS) AF: 0.0784 AC: 3562 AN: 45410

European-Finnish (FIN) AF: 0.396 AC: 13932 AN: 35172

Middle Eastern (MID) AF: 0.306 AC: 1061 AN: 3472

European-Non Finnish (NFE) AF: 0.172 AC: 95163 AN: 551734

Other (OTH) AF: 0.228 AC: 7433 AN: 32650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.466 AC: 16539 AN: 35476

American (AMR) AF: 0.396 AC: 4786 AN: 12100

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1263 AN: 2856

East Asian (EAS) AF: 0.385 AC: 1574 AN: 4090

South Asian (SAS) AF: 0.382 AC: 1437 AN: 3758

European-Finnish (FIN) AF: 0.445 AC: 3783 AN: 8498

Middle Eastern (MID) AF: 0.453 AC: 107 AN: 236

European-Non Finnish (NFE) AF: 0.451 AC: 25397 AN: 56324

Other (OTH) AF: 0.435 AC: 738 AN: 1696

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.334 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		1.1
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs72492997; hg19: chr3-10088266; COSMIC: COSV55036171; COSMIC: COSV55036171;