rs36070315

Positions:

chr3-10063832-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001018115.3(FANCD2):c.1868A>C(p.Gln623Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0041 in 1,614,084 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 113 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 28 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 6.76

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004644096).

BP6

Variant 3-10063832-A-C is Benign according to our data. Variant chr3-10063832-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 134314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10063832-A-C is described in Lovd as [Benign]. Variant chr3-10063832-A-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3 linkuse as main transcript	c.1868A>C	p.Gln623Pro	missense_variant	21/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 linkuse as main transcript	c.1868A>C	p.Gln623Pro	missense_variant	21/44		NM_001018115.3	ENSP00000502379	P2	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3456

AN:

152162

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0791

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00845

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.00548

AC:

1377

AN:

251436

Hom.:

AF XY:

0.00394

AC XY:

535

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0767

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00216

AC:

3156

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1357

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0762

Gnomad4 AMR exome

AF:

0.00364

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.00484

GnomAD4 genome

AF:

0.0227

AC:

3461

AN:

152280

Hom.:

113

Cov.:

AF XY:

0.0221

AC XY:

1643

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0790

Gnomad4 AMR

AF:

0.00843

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0268

ESP6500AA

AF:

0.0831

AC:

366

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00685

AC:

832

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2017	- -

Fanconi anemia complementation group D2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Fanconi anemia complementation group A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

FANCD2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

D;D;.

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M

MutationTaster

Benign

0.95

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Benign

0.16

Sift

Benign

0.12

T;T;T

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.99

.;D;D

Vest4

0.58

MVP

0.82

MPC

0.51

ClinPred

0.024

GERP RS

5.6

Varity_R

0.58

gMVP

0.63

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