3-10046601-T-G

Position:

chr3-10046601-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001018115.3(FANCD2):c.1156T>G(p.Phe386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 151,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 0 hom., cov: 47)

Exomes 𝑓: 0.00059 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0210

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008343905).

BP6

Variant 3-10046601-T-G is Benign according to our data. Variant chr3-10046601-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 241729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10046601-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00473 (715/151072) while in subpopulation AMR AF= 0.0202 (298/14764). AF 95% confidence interval is 0.0183. There are 0 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 47. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3 linkuse as main transcript	c.1156T>G	p.Phe386Val	missense_variant	15/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 linkuse as main transcript	c.1156T>G	p.Phe386Val	missense_variant	15/44		NM_001018115.3	ENSP00000502379	P2	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

710

AN:

150960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.00466

Gnomad EAS

AF:

0.00330

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00522

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00532

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

250164

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000591

AC:

858

AN:

1450622

Hom.:

Cov.:

AF XY:

0.000622

AC XY:

449

AN XY:

721876

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00581

Gnomad4 ASJ exome

AF:

0.000848

Gnomad4 EAS exome

AF:

0.00132

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00159

Gnomad4 NFE exome

AF:

0.000340

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00473

AC:

715

AN:

151072

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

361

AN XY:

73882

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.0202

Gnomad4 ASJ

AF:

0.00466

Gnomad4 EAS

AF:

0.00331

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00522

Gnomad4 NFE

AF:

0.00395

Gnomad4 OTH

AF:

0.00527

Alfa

AF:

0.00434

Hom.:

ExAC

AF:

0.00335

AC:

407

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2016

- -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.10

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.87

D;D;.

MetaRNN

Benign

0.0083

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.038

D;D;D

Sift4G

Uncertain

0.056

T;T;T

Polyphen

0.16

.;B;B

Vest4

0.45

MVP

0.31

MPC

0.22

ClinPred

0.028

GERP RS

-1.8

Varity_R

0.26

gMVP

0.25

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