NM_001018115.3:c.1214A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001018115.3(FANCD2):c.1214A>G(p.Asn405Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 0 hom., cov: 49)

Exomes 𝑓: 0.39 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.211

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024337769).

BP6

Variant 3-10046659-A-G is Benign according to our data. Variant chr3-10046659-A-G is described in ClinVar as [Benign]. Clinvar id is 342263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10046659-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.1214A>G	p.Asn405Ser	missense_variant	Exon 15 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.1214A>G	p.Asn405Ser	missense_variant	Exon 15 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

65086

AN:

141890

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.478

Gnomad AMI

AF:

0.442

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.463

Gnomad MID

AF:

0.460

Gnomad NFE

AF:

0.462

Gnomad OTH

AF:

0.452

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff

AF:

0.389

AC:

373029

AN:

959700

Hom.:

Cov.:

AF XY:

0.387

AC XY:

184921

AN XY:

478068

show subpopulations

Gnomad4 AFR exome

AF:

0.430

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.386

Gnomad4 EAS exome

AF:

0.317

Gnomad4 SAS exome

AF:

0.254

Gnomad4 FIN exome

AF:

0.445

Gnomad4 NFE exome

AF:

0.399

Gnomad4 OTH exome

AF:

0.397

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.459

AC:

65132

AN:

141990

Hom.:

Cov.:

AF XY:

0.457

AC XY:

31673

AN XY:

69286

show subpopulations

Gnomad4 AFR

AF:

0.478

Gnomad4 AMR

AF:

0.420

Gnomad4 ASJ

AF:

0.457

Gnomad4 EAS

AF:

0.411

Gnomad4 SAS

AF:

0.410

Gnomad4 FIN

AF:

0.463

Gnomad4 NFE

AF:

0.462

Gnomad4 OTH

AF:

0.453

Alfa

AF:

0.368

Hom.:

ExAC

AF:

0.412

AC:

50070

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Benign:2

Jan 13, 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. -

Jan 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia

Benign:1

Aug 02, 2017

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

0.077

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.078

.;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.85

T;T;.

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.98

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.81

T;T;T

Polyphen

0.022

.;B;B

Vest4

0.042

MPC

0.12

ClinPred

0.00058

GERP RS

0.31

Varity_R

0.032

gMVP

0.081

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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