rs35782247

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.1367T>G(p.Leu456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,613,156 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. L456I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 6 hom., cov: 45)

Exomes 𝑓: 0.0027 ( 3 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.53

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 was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0034121275).

BP6

Variant 3-10048005-T-G is Benign according to our data. Variant chr3-10048005-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10048005-T-G is described in Lovd as [Benign]. Variant chr3-10048005-T-G is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.1367T>G	p.Leu456Arg	missense_variant	Exon 16 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.1367T>G	p.Leu456Arg	missense_variant	Exon 16 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

4080

AN:

151728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0943

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.00705

AC:

1772

AN:

251396

AF XY:

0.00518

show subpopulations

Gnomad AFR exome

AF:

0.0988

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00268

AC:

3921

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1712

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0945

AC:

3124

AN:

33072

Gnomad4 AMR exome

AF:

0.00447

AC:

200

AN:

44702

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26130

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39692

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86254

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53414

Gnomad4 NFE exome

AF:

0.000125

AC:

139

AN:

1111976

Gnomad4 Remaining exome

AF:

0.00713

AC:

430

AN:

60344

Heterozygous variant carriers

251

503

754

1006

1257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.0269

AC:

4086

AN:

151846

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1964

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0942

AC:

0.0942022

AN:

0.0942022

Gnomad4 AMR

AF:

0.0101

AC:

0.0101281

AN:

0.0101281

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.000413907

AN:

0.000413907

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000220

AC:

0.000220439

AN:

0.000220439

Gnomad4 OTH

AF:

0.0222

AC:

0.0222327

AN:

0.0222327

Heterozygous variant carriers

236

472

709

945

1181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

120

160

200

<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:

0.00690

Hom.:

ESP6500AA

AF:

0.104

AC:

458

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00874

AC:

1061

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Pathogenic:1Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 28, 2020

Leiden Open Variation Database

Significance:Pathogenic

Review Status:flagged submission

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not provided

Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21356188, 27153395, 24728327, 20981092, 17436244) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3Other:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

- -

Dec 20, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FANCD2 c.1367T>G (p.Leu456Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 251396 control chromosomes, predominantly at a frequency of 0.099 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 204.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with conflicting interpretation. Based on the evidence outlined above, the variant was classified as benign. -

Fanconi anemia

Benign:2

Sep 10, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Oct 21, 2024

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

0.13

BayesDel_addAF

Benign

0.0056

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

.;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T;.

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.99

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

1.0

.;D;D

Vest4

0.81

MVP

0.84

MPC

0.48

ClinPred

0.025

GERP RS

5.7

Varity_R

0.34

gMVP

0.51

Mutation Taster

=98/2

polymorphism (auto)

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