2-19931318-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020779.4(WDR35):c.2915A>G(p.Glu972Gly) variant causes a missense change. The variant allele was found at a frequency of 0.367 in 1,612,832 control chromosomes in the GnomAD database, including 114,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8350 hom., cov: 31)

Exomes 𝑓: 0.37 ( 105957 hom. )

Consequence

WDR35
NM_020779.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.85

Variant links:

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

WDR35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037181973).

BP6

Variant 2-19931318-T-C is Benign according to our data. Variant chr2-19931318-T-C is described in ClinVar as [Benign]. Clinvar id is 167844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-19931318-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR35	NM_001006657.2 link	c.2948A>G	p.Glu983Gly	missense_variant	Exon 25 of 28	ENST00000345530.8	NP_001006658.1	Q9P2L0-1
WDR35	NM_020779.4 link	c.2915A>G	p.Glu972Gly	missense_variant	Exon 24 of 27	ENST00000281405.9	NP_065830.2	Q9P2L0-2
WDR35	XM_011533007.3 link	c.1643A>G	p.Glu548Gly	missense_variant	Exon 14 of 17		XP_011531309.1
WDR35	XR_426989.4 link	n.2905A>G		non_coding_transcript_exon_variant	Exon 24 of 25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 link	c.2948A>G	p.Glu983Gly	missense_variant	Exon 25 of 28	1	NM_001006657.2	ENSP00000314444.5		Q9P2L0-1
WDR35	ENST00000281405.9 link	c.2915A>G	p.Glu972Gly	missense_variant	Exon 24 of 27	1	NM_020779.4	ENSP00000281405.5		Q9P2L0-2

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47265

AN:

151702

Hom.:

8353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.421

Gnomad EAS

AF:

0.0990

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.340

GnomAD3 exomes

AF:

0.337

AC:

84770

AN:

251262

Hom.:

15774

AF XY:

0.338

AC XY:

45950

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.0979

Gnomad SAS exome

AF:

0.233

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.404

Gnomad OTH exome

AF:

0.370

GnomAD4 exome

AF:

0.373

AC:

545403

AN:

1461012

Hom.:

105957

Cov.:

AF XY:

0.371

AC XY:

269614

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.146

Gnomad4 AMR exome

AF:

0.362

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.0948

Gnomad4 SAS exome

AF:

0.234

Gnomad4 FIN exome

AF:

0.392

Gnomad4 NFE exome

AF:

0.400

Gnomad4 OTH exome

AF:

0.356

GnomAD4 genome

AF:

0.311

AC:

47255

AN:

151820

Hom.:

8350

Cov.:

AF XY:

0.307

AC XY:

22778

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.344

Gnomad4 ASJ

AF:

0.421

Gnomad4 EAS

AF:

0.0986

Gnomad4 SAS

AF:

0.223

Gnomad4 FIN

AF:

0.396

Gnomad4 NFE

AF:

0.402

Gnomad4 OTH

AF:

0.335

Alfa

AF:

0.382

Hom.:

26769

Bravo

AF:

0.305

TwinsUK

AF:

0.406

AC:

1506

ALSPAC

AF:

0.417

AC:

1606

ESP6500AA

AF:

0.161

AC:

709

ESP6500EA

AF:

0.403

AC:

3463

ExAC

AF:

0.332

AC:

40318

Asia WGS

AF:

0.157

AC:

549

AN:

3476

EpiCase

AF:

0.407

EpiControl

AF:

0.411

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cranioectodermal dysplasia 2

Benign:3

May 28, 2019

Mendelics

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Short-rib thoracic dysplasia 7 with or without polydactyly

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

0.021

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.22

Sift

Benign

0.077

T;T

Sift4G

Benign

0.068

T;T

Polyphen

0.35

B;B

Vest4

0.13

MPC

0.33

ClinPred

0.047

GERP RS

4.8

Varity_R

0.11

gMVP

0.32

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