rs3864017

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001018115.3(FANCD2):c.2141C>T(p.Pro714Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,536,518 control chromosomes in the GnomAD database, including 14,248 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P714P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 1870 hom., cov: 32)

Exomes 𝑓: 0.14 ( 12378 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -0.0900

Publications

37 publications found

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 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=0.0033615232).

BP6

Variant 3-10064848-C-T is Benign according to our data. Variant chr3-10064848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.2141C>T	p.Pro714Leu	missense_variant	Exon 23 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.2141C>T	p.Pro714Leu	missense_variant	Exon 23 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

27645

AN:

147016

Hom.:

1866

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.0626

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.132

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.142

AC:

34399

AN:

242424

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.261

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.0524

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.145

AC:

201031

AN:

1389386

Hom.:

12378

Cov.:

AF XY:

0.145

AC XY:

100652

AN XY:

692730

show subpopulations

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

African (AFR)

AF:

0.270

AC:

8312

AN:

30780

American (AMR)

AF:

0.146

AC:

6388

AN:

43654

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

3776

AN:

25428

East Asian (EAS)

AF:

0.0514

AC:

2020

AN:

39312

South Asian (SAS)

AF:

0.165

AC:

13856

AN:

84036

European-Finnish (FIN)

AF:

0.121

AC:

6318

AN:

52124

Middle Eastern (MID)

AF:

0.147

AC:

805

AN:

5458

European-Non Finnish (NFE)

AF:

0.144

AC:

151073

AN:

1050814

Other (OTH)

AF:

0.147

AC:

8483

AN:

57780

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.372

Heterozygous variant carriers

6963

13925

20888

27850

34813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5208

10416

15624

20832

26040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.188

AC:

27669

AN:

147132

Hom.:

1870

Cov.:

AF XY:

0.184

AC XY:

13178

AN XY:

71752

show subpopulations

African (AFR)

AF:

0.284

AC:

11504

AN:

40552

American (AMR)

AF:

0.143

AC:

2103

AN:

14734

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

509

AN:

3344

East Asian (EAS)

AF:

0.0625

AC:

323

AN:

5166

South Asian (SAS)

AF:

0.162

AC:

751

AN:

4650

European-Finnish (FIN)

AF:

0.122

AC:

1202

AN:

9854

Middle Eastern (MID)

AF:

0.125

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.162

AC:

10666

AN:

65650

Other (OTH)

AF:

0.168

AC:

340

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

975

1951

2926

3902

4877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.165

Hom.:

509

ExAC

AF:

0.154

AC:

18760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Benign:4

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. -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2019

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30250602) -

Fanconi anemia complementation group A

Benign:1

May 28, 2019

Mendelics

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

0.061

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.1

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.063

.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.25

T;T;.

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-0.090

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.028

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.0010

.;B;B

Vest4

0.052

MPC

0.15

ClinPred

0.0018

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.15

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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