rs35594075

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001018115.3(FANCD2):c.2712C>T(p.Asn904Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,604,542 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 227 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 202 hom. )

Consequence

FANCD2
NM_001018115.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.435

Publications

4 publications found

Variant links:

COSMIC-nc: COSV55035000

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 3-10073359-C-T is Benign according to our data. Variant chr3-10073359-C-T is described in ClinVar as Benign. ClinVar VariationId is 257075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.435 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.2712C>T	p.Asn904Asn	synonymous_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.2712C>T	p.Asn904Asn	synonymous_variant	Exon 28 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4483

AN:

152028

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.00737

AC:

1853

AN:

251444

AF XY:

0.00532

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00379

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:

0.00291

AC:

4229

AN:

1452396

Hom.:

202

Cov.:

AF XY:

0.00254

AC XY:

1838

AN XY:

723254

show subpopulations

African (AFR)

AF:

0.102

AC:

3399

AN:

33234

American (AMR)

AF:

0.00461

AC:

206

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000135

AC:

149

AN:

1103448

Other (OTH)

AF:

0.00734

AC:

441

AN:

60052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

178

357

535

714

892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.0295

AC:

4494

AN:

152146

Hom.:

227

Cov.:

AF XY:

0.0289

AC XY:

2149

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.103

AC:

4272

AN:

41484

American (AMR)

AF:

0.0103

AC:

157

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68018

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

205

410

614

819

1024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0138

Hom.:

Bravo

AF:

0.0343

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Benign: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

- -

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. -

not provided

Benign:3

Apr 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 02, 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

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.70

(source)

DANN

Benign

0.42

PhyloP100

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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