3-10049351-T-C

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.1414-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,117,110 control chromosomes in the GnomAD database, including 48,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 13140 hom., cov: 30)

Exomes 𝑓: 0.28 ( 35531 hom. )

Consequence

FANCD2
NM_001018115.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.483

Publications

9 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 (BayesDel_noAF=-0.91).

BP6

Variant 3-10049351-T-C is Benign according to our data. Variant chr3-10049351-T-C is described in ClinVar as Benign. ClinVar VariationId is 257068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.1414-23T>C		intron_variant	Intron 16 of 43	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.1414-23T>C		intron_variant	Intron 16 of 43		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

55328

AN:

118078

Hom.:

13119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.774

Gnomad AMI

AF:

0.359

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.414

GnomAD2 exomes

AF:

0.206

AC:

39456

AN:

191370

AF XY:

0.191

show subpopulations

Gnomad AFR exome

AF:

0.759

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.0914

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.279

AC:

278499

AN:

998934

Hom.:

35531

Cov.:

AF XY:

0.278

AC XY:

138905

AN XY:

499934

show subpopulations

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

African (AFR)

AF:

0.779

AC:

21386

AN:

27460

American (AMR)

AF:

0.232

AC:

7914

AN:

34166

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

6987

AN:

19682

East Asian (EAS)

AF:

0.132

AC:

3925

AN:

29676

South Asian (SAS)

AF:

0.222

AC:

14683

AN:

66174

European-Finnish (FIN)

AF:

0.250

AC:

9549

AN:

38134

Middle Eastern (MID)

AF:

0.314

AC:

1326

AN:

4224

European-Non Finnish (NFE)

AF:

0.271

AC:

199603

AN:

736590

Other (OTH)

AF:

0.306

AC:

13126

AN:

42828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.340

Heterozygous variant carriers

11587

23174

34760

46347

57934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6100

12200

18300

24400

30500

<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:

0.469

AC:

55390

AN:

118176

Hom.:

13140

Cov.:

AF XY:

0.456

AC XY:

26216

AN XY:

57496

show subpopulations

African (AFR)

AF:

0.774

AC:

28570

AN:

36906

American (AMR)

AF:

0.327

AC:

3804

AN:

11628

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

1030

AN:

2666

East Asian (EAS)

AF:

0.186

AC:

683

AN:

3666

South Asian (SAS)

AF:

0.260

AC:

930

AN:

3572

European-Finnish (FIN)

AF:

0.283

AC:

2094

AN:

7390

Middle Eastern (MID)

AF:

0.373

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.347

AC:

17283

AN:

49820

Other (OTH)

AF:

0.412

AC:

662

AN:

1606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

1057

2115

3172

4230

5287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.357

Hom.:

1361

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia complementation group D2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

-0.91

CADD

Benign

0.41

(source)

DANN

Benign

0.67

PhyloP100

-0.48

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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