rs6785756

Variant names:

• chr3-10049469-C-T
• rs6785756
• NM_001018115.3:c.1509C>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.1509C>T​(p.Asn503Asn) 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:6
• Conservation: PhyloP100: 0.872
• Publications: 7 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=-0.74).
• BP6: Variant 3-10049469-C-T is Benign according to our data. Variant chr3-10049469-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1509C>T	p.Asn503Asn	synonymous_variant	Exon 17 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1509C>T	p.Asn503Asn	synonymous_variant	Exon 17 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 21029 AN: 132134 Hom.: 1066 Cov.: 32

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

GnomAD2 exomes AF: 0.0300 AC: 7152 AN: 238040 AF XY: 0.0284

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 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

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

African (AFR) AF: 0.130 AC: 3390 AN: 26166

American (AMR) AF: 0.0566 AC: 2304 AN: 40686

Ashkenazi Jewish (ASJ) AF: 0.0641 AC: 1492 AN: 23278

East Asian (EAS) AF: 0.0282 AC: 1070 AN: 37906

South Asian (SAS) AF: 0.0929 AC: 7271 AN: 78306

European-Finnish (FIN) AF: 0.0455 AC: 2210 AN: 48540

Middle Eastern (MID) AF: 0.0491 AC: 247 AN: 5032

European-Non Finnish (NFE) AF: 0.0380 AC: 36549 AN: 962962

Other (OTH) AF: 0.0594 AC: 3117 AN: 52500

⚠️ 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: AS_VQSR AF: 0.159 AC: 21047 AN: 132256 Hom.: 1068 Cov.: 32 AF XY: 0.153 AC XY: 9907 AN XY: 64558

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

African (AFR) AF: 0.261 AC: 9045 AN: 34630

American (AMR) AF: 0.117 AC: 1597 AN: 13596

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 384 AN: 3034

East Asian (EAS) AF: 0.0519 AC: 252 AN: 4856

South Asian (SAS) AF: 0.144 AC: 595 AN: 4146

European-Finnish (FIN) AF: 0.0896 AC: 830 AN: 9266

Middle Eastern (MID) AF: 0.140 AC: 36 AN: 258

European-Non Finnish (NFE) AF: 0.132 AC: 7904 AN: 59864

Other (OTH) AF: 0.135 AC: 251 AN: 1856

⚠️ 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: 0.127 Hom.: 171

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.74
CADD	Benign	8.1
DANN	Benign	0.57
PhyloP100		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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