rs45510294

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001018115.3(FANCD2):c.78A>C(p.Gln26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,120 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q26P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8

Conservation

PhyloP100: -0.128

Publications

10 publications found

Variant links:

COSMIC-nc: COSV55036019

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016909897).

BP6

Variant 3-10032845-A-C is Benign according to our data. Variant chr3-10032845-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456361.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.78A>C	p.Gln26His	missense_variant	Exon 3 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 link	c.78A>C	p.Gln26His	missense_variant	Exon 3 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000766

AC:

192

AN:

250632

AF XY:

0.000826

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.00108

AC:

1577

AN:

1460818

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

771

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33458

American (AMR)

AF:

0.000179

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00211

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39632

South Asian (SAS)

AF:

0.000302

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00126

AC:

1403

AN:

1111394

Other (OTH)

AF:

0.000961

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000729

AC:

111

AN:

152302

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41562

American (AMR)

AF:

0.000458

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00116

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000568

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 13, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed without a second FANCD2 variant in a family with thrombocytopenia who had a different genetic etiology for the phenotype (PMID: 27931139); This variant is associated with the following publications: (PMID: 32546565, 36604647, 30256826, 27931139)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FANCD2: BP1, BP4

Fanconi anemia complementation group D2

Uncertain:2Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fanconi anemia

Benign:2

Oct 29, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Feb 17, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the FANCD2 gene demonstrated a sequence change, c.78A>C, in exon 3 that results in an amino acid change, p.Gln26His. This sequence change does not appear to have been previously described in patients with FANCD2-related disorders and has been described in the gnomAD database with a frequency of 0.21% in the Ashkenazi Jewish sub-population (dbSNP rs45510294). The p.Gln26His change affects a poorly conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln26His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gln26His change remains unknown at this time.

FANCD2-related disorder

Benign:1

Jan 12, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.9

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0

.;T;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.64

T;T;.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

M;M;M;M

PhyloP100

-0.13

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.069

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Vest4

0.17

ClinPred

0.0082

GERP RS

-1.7

Varity_R

0.037

gMVP

0.23

Mutation Taster

=96/4

polymorphism

(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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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