rs2272125

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001018115.3(FANCD2):c.4098T>G(p.Leu1366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,613,254 control chromosomes in the GnomAD database, including 29,962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5950 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24012 hom. )

Consequence

FANCD2
NM_001018115.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.97

Variant links:

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 links:

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

FANCD2OS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 3-10096385-T-G is Benign according to our data. Variant chr3-10096385-T-G is described in ClinVar as [Benign]. Clinvar id is 257081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10096385-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3 linkuse as main transcript	c.4098T>G	p.Leu1366=	synonymous_variant	42/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1 linkuse as main transcript	c.4098T>G	p.Leu1366=	synonymous_variant	42/44		NM_001018115.3	P2	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36745

AN:

152002

Hom.:

5942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.463

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.0896

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.207

GnomAD3 exomes

AF:

0.181

AC:

45403

AN:

251422

Hom.:

5040

AF XY:

0.178

AC XY:

24123

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.478

Gnomad AMR exome

AF:

0.182

Gnomad ASJ exome

AF:

0.159

Gnomad EAS exome

AF:

0.0893

Gnomad SAS exome

AF:

0.208

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.173

AC:

252509

AN:

1461134

Hom.:

24012

Cov.:

AF XY:

0.173

AC XY:

125520

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.474

Gnomad4 AMR exome

AF:

0.186

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.0760

Gnomad4 SAS exome

AF:

0.210

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.166

Gnomad4 OTH exome

AF:

0.181

GnomAD4 genome

AF:

0.242

AC:

36782

AN:

152120

Hom.:

5950

Cov.:

AF XY:

0.236

AC XY:

17572

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.463

Gnomad4 AMR

AF:

0.173

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.0894

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.162

Gnomad4 OTH

AF:

0.207

Alfa

AF:

0.198

Hom.:

2567

Bravo

AF:

0.258

Asia WGS

AF:

0.147

AC:

513

AN:

3478

EpiCase

AF:

0.163

EpiControl

AF:

0.159

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	Mar 06, 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 specified

Benign:2

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 07, 2016	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2019

This variant is associated with the following publications: (PMID: 16679306) -

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

-0.51

Cadd

Benign

4.2

Dann

Benign

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over