rs149667250

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020779.4(WDR35):c.2566G>T(p.Val856Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,613,700 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 82 hom. )

Consequence

WDR35
NM_020779.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.70

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:

WDR35 (HGNC:):

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=0.004893422).

BP6

Variant 2-19933493-C-A is Benign according to our data. Variant chr2-19933493-C-A is described in ClinVar as [Benign]. Clinvar id is 93463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00186 (283/152300) while in subpopulation AMR AF= 0.0171 (261/15288). AF 95% confidence interval is 0.0154. There are 3 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2 linkuse as main transcript	c.2599G>T	p.Val867Phe	missense_variant	23/28	ENST00000345530.8	NP_001006658.1	Q9P2L0-1
WDR35	NM_020779.4 linkuse as main transcript	c.2566G>T	p.Val856Phe	missense_variant	22/27	ENST00000281405.9	NP_065830.2	Q9P2L0-2
WDR35	XM_011533007.3 linkuse as main transcript	c.1294G>T	p.Val432Phe	missense_variant	12/17		XP_011531309.1
WDR35	XR_426989.4 linkuse as main transcript	n.2656G>T		non_coding_transcript_exon_variant	22/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WDR35	ENST00000345530.8 linkuse as main transcript	c.2599G>T	p.Val867Phe	missense_variant	23/28	1	NM_001006657.2	ENSP00000314444.5	Q9P2L0-1
WDR35	ENST00000281405.9 linkuse as main transcript	c.2566G>T	p.Val856Phe	missense_variant	22/27	1	NM_020779.4	ENSP00000281405.5	Q9P2L0-2
WDR35	ENST00000414212.5 linkuse as main transcript	n.2603G>T		non_coding_transcript_exon_variant	23/28	5		ENSP00000390802.1	F8WB94
WDR35	ENST00000445063.5 linkuse as main transcript	n.*1271+1978G>T		intron_variant		2		ENSP00000390105.1	H7BZK8

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00767

AC:

1926

AN:

251120

Hom.:

AF XY:

0.00581

AC XY:

788

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0548

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00156

AC:

2276

AN:

1461400

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

938

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0490

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00186

AC:

283

AN:

152300

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00452

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00631

AC:

766

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 10, 2013

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cranioectodermal dysplasia 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Short-rib thoracic dysplasia 7 with or without polydactyly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.042

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.098

Sift

Benign

0.27

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0070

B;B

Vest4

0.61

MVP

0.18

MPC

0.63

ClinPred

0.029

GERP RS

3.4

Varity_R

0.17

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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