rs34046352

Positions:

• chr3-10043852-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001018115.3(FANCD2):​c.1122A>G​(p.Val374Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 151,510 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (236 hom., cov: 34)
  • Exomes 𝑓: 0.10 (155 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0460

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-10043852-A-G is Benign according to our data. Variant chr3-10043852-A-G is described in ClinVar as [Benign]. Clinvar id is 257065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10043852-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.046 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1122A>G	p.Val374Val	synonymous_variant	14/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1122A>G	p.Val374Val	synonymous_variant	14/44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29209 AN: 151394 Hom.: 235 Cov.: 34

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.171

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0998 AC: 128878 AN: 1291182 Hom.: 155 Cov.: 31 AF XY: 0.102 AC XY: 65695 AN XY: 645390

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.0471

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0906

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.193 AC: 29240 AN: 151510 Hom.: 236 Cov.: 34 AF XY: 0.188 AC XY: 13895 AN XY: 74088

Gnomad4 AFR AF: 0.335

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0603

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.170

Alfa AF: 0.170 Hom.: 29

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2016	- -

Fanconi anemia complementation group D2 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 provided Benign:2

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

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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	-0.92
CADD	Benign	1.2
DANN	Benign	0.58

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: rs34046352; hg19: chr3-10085536; COSMIC: COSV55037937; COSMIC: COSV55037937;