rs6785756

chr3-10049469-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001018115.3(FANCD2):c.1509C>T(p.Asn503=) 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1068 hom., cov: 32)
  • Exomes 𝑓: 0.045 (3032 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.872

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-10049469-C-T is Benign according to our data. Variant chr3-10049469-C-T is described in ClinVar as [Benign]. Clinvar id is 257070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.872 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 638 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.1509C>T	p.Asn503=	synonymous_variant	17/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.1509C>T	p.Asn503=	synonymous_variant	17/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 21029 AN: 132134 Hom.: 1066 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.145

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.0300 AC: 7152 AN: 238040 Hom.: 638 AF XY: 0.0284 AC XY: 3669 AN XY: 128990

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0213

Gnomad SAS exome AF: 0.0371

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0372

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0452 AC: 57650 AN: 1275376 Hom.: 3032 Cov.: 34 AF XY: 0.0473 AC XY: 30103 AN XY: 636740

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.0566

Gnomad4 ASJ exome AF: 0.0641

Gnomad4 EAS exome AF: 0.0282

Gnomad4 SAS exome AF: 0.0929

Gnomad4 FIN exome AF: 0.0455

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0594

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.159 AC: 21047 AN: 132256 Hom.: 1068 Cov.: 32 AF XY: 0.153 AC XY: 9907 AN XY: 64558

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.135

Alfa AF: 0.127 Hom.: 171

ClinVar

Significance: 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

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 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	-0.74
Cadd	Benign	8.1
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6785756; hg19: chr3-10091153; COSMIC: COSV55032395; COSMIC: COSV55032395;