rs72492998

Variant names:

• chr3-10046624-T-C
• rs72492998
• NM_001018115.3:c.1179T>C

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.1179T>C​(p.Thr393Thr) 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:6
• Conservation: PhyloP100: -0.281
• Publications: 15 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=-0.52).
• BP6: Variant 3-10046624-T-C is Benign according to our data. Variant chr3-10046624-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 342262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.281 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1179T>C	p.Thr393Thr	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.1179T>C	p.Thr393Thr	synonymous_variant	Exon 15 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 63815 AN: 139174 Hom.: 0 Cov.: 48

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

GnomAD2 exomes AF: 0.236 AC: 35999 AN: 152394 AF XY: 0.237

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.180

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

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

African (AFR) AF: 0.432 AC: 8802 AN: 20364

American (AMR) AF: 0.287 AC: 7740 AN: 27010

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 6276 AN: 15970

East Asian (EAS) AF: 0.315 AC: 8516 AN: 27052

South Asian (SAS) AF: 0.254 AC: 11095 AN: 43744

European-Finnish (FIN) AF: 0.447 AC: 18407 AN: 41178

Middle Eastern (MID) AF: 0.413 AC: 1627 AN: 3942

European-Non Finnish (NFE) AF: 0.394 AC: 258364 AN: 656206

Other (OTH) AF: 0.394 AC: 14626 AN: 37144

⚠️ 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: 0.459 AC: 63860 AN: 139274 Hom.: 0 Cov.: 48 AF XY: 0.457 AC XY: 31050 AN XY: 67974

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

African (AFR) AF: 0.478 AC: 18371 AN: 38434

American (AMR) AF: 0.420 AC: 5706 AN: 13594

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1438 AN: 3154

East Asian (EAS) AF: 0.409 AC: 1871 AN: 4580

South Asian (SAS) AF: 0.409 AC: 1749 AN: 4278

European-Finnish (FIN) AF: 0.462 AC: 4418 AN: 9566

Middle Eastern (MID) AF: 0.462 AC: 123 AN: 266

European-Non Finnish (NFE) AF: 0.462 AC: 28953 AN: 62656

Other (OTH) AF: 0.452 AC: 861 AN: 1906

⚠️ 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: 0.387 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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: Likely 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	-0.52
CADD	Benign	7.9
DANN	Benign	0.69
PhyloP100		-0.28
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs72492998; hg19: chr3-10088308; COSMIC: COSV55032659; COSMIC: COSV55032659;