rs72492998

chr3-10046624-T-C

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.1179T>C(p.Thr393=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (0 hom., cov: 48)
  • Exomes 𝑓: 0.38 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.281

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-10046624-T-C is Benign according to our data. Variant chr3-10046624-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 342262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10046624-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.281 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.1179T>C	p.Thr393=	synonymous_variant	15/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.1179T>C	p.Thr393=	synonymous_variant	15/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 63815 AN: 139174 Hom.: 0 Cov.: 48 FAILED QC

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.458

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.451

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.384 AC: 335453 AN: 872610 Hom.: 0 Cov.: 59 AF XY: 0.384 AC XY: 167682 AN XY: 436850

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.287

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.394

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.459 AC: 63860 AN: 139274 Hom.: 0 Cov.: 48 AF XY: 0.457 AC XY: 31050 AN XY: 67974

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.452

Alfa AF: 0.387 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 04, 2017

- -

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. -

Fanconi anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 02, 2017

- -

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	-0.52
Cadd	Benign	7.9
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72492998; hg19: chr3-10088308; COSMIC: COSV55032659; COSMIC: COSV55032659;