NM_001018115.3:c.2702G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001018115.3(FANCD2):c.2702G>T(p.Gly901Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,611,202 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G901S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 61 hom., cov: 32)

Exomes 𝑓: 0.031 ( 799 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 1.64

Publications

18 publications found

Variant links:

COSMIC-nc: COSV55033803

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

FANCD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039370656).

BP6

Variant 3-10073349-G-T is Benign according to our data. Variant chr3-10073349-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 134318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3364/152232) while in subpopulation NFE AF = 0.0346 (2353/68032). AF 95% confidence interval is 0.0334. There are 61 homozygotes in GnomAd4. There are 1590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.2702G>T	p.Gly901Val	missense_variant	Exon 28 of 44	ENST00000675286.1	NP_001018125.1	Q9BXW9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 link	c.2702G>T	p.Gly901Val	missense_variant	Exon 28 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3364

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00592

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0249

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0346

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0218

AC:

5486

AN:

251444

AF XY:

0.0213

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0230

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

AF:

0.0307

AC:

44743

AN:

1458970

Hom.:

799

Cov.:

AF XY:

0.0300

AC XY:

21751

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.00470

AC:

157

AN:

33424

American (AMR)

AF:

0.0183

AC:

819

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

616

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00490

AC:

422

AN:

86204

European-Finnish (FIN)

AF:

0.0230

AC:

1226

AN:

53406

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0359

AC:

39809

AN:

1109380

Other (OTH)

AF:

0.0279

AC:

1680

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1881

3762

5642

7523

9404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0221

AC:

3364

AN:

152232

Hom.:

Cov.:

AF XY:

0.0214

AC XY:

1590

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00590

AC:

245

AN:

41528

American (AMR)

AF:

0.0234

AC:

358

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0249

AC:

264

AN:

10586

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0346

AC:

2353

AN:

68032

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0299

Hom.:

286

Bravo

AF:

0.0214

TwinsUK

AF:

0.0364

AC:

135

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0347

AC:

298

ExAC

AF:

0.0220

AC:

2673

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0277

EpiControl

AF:

0.0308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Benign:3

Jan 12, 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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 31, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 04, 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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.081

.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

T;T;.

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N

PhyloP100

1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.093

T;T;T

Polyphen

0.13

.;B;B

Vest4

0.20

MPC

0.22

ClinPred

0.022

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.15

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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NM_001018115.3:c.2702G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over