rs143343508

Positions:

chr2-19966735-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000281405.9(WDR35):c.1183A>T(p.Asn395Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00234 in 1,613,800 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 4 hom. )

Consequence

WDR35
ENST00000281405.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:2

Conservation

PhyloP100: 4.93

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014500916).

BP6

Variant 2-19966735-T-A is Benign according to our data. Variant chr2-19966735-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288569.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (208/152314) while in subpopulation NFE AF= 0.0024 (163/68020). AF 95% confidence interval is 0.0021. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2 linkuse as main transcript	c.1183A>T	p.Asn395Tyr	missense_variant	10/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4 linkuse as main transcript	c.1183A>T	p.Asn395Tyr	missense_variant	10/27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 linkuse as main transcript	c.1183A>T	p.Asn395Tyr	missense_variant	10/28	1	NM_001006657.2	ENSP00000314444	A1	Q9P2L0-1
WDR35	ENST00000281405.9 linkuse as main transcript	c.1183A>T	p.Asn395Tyr	missense_variant	10/27	1	NM_020779.4	ENSP00000281405	P3	Q9P2L0-2
WDR35	ENST00000414212.5 linkuse as main transcript	c.1183A>T	p.Asn395Tyr	missense_variant, NMD_transcript_variant	10/28	5		ENSP00000390802
WDR35	ENST00000445063.5 linkuse as main transcript	c.721A>T	p.Asn241Tyr	missense_variant, NMD_transcript_variant	5/18	2		ENSP00000390105

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00172

AC:

432

AN:

251214

Hom.:

AF XY:

0.00194

AC XY:

263

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00244

AC:

3564

AN:

1461486

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1836

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.000956

Gnomad4 NFE exome

AF:

0.00285

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.00137

AC:

208

AN:

152314

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00217

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00183

AC:

222

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	The WDR35 c.1183A>T; p.Asn395Tyr variant (rs143343508) is reported in a fetus affected with short-rib polydactyly syndromes without biallelic pathogenic findings, no functional or segregation data were provided (Zhang 2018). This variant is also reported in ClinVar (Variation ID: 288569) and is found in the non-Finnish European population with an allele frequency of 0.27% (342/128,986 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.26). Due to limited information, the clinical significance of the p.Asn395Tyr variant is uncertain at this time. References: Zhang et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Short-rib thoracic dysplasia 6 with or without polydactyly

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

WDR35-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2024

The WDR35 c.1183A>T variant is predicted to result in the amino acid substitution p.Asn395Tyr. This variant was reported in an individual with short rib-polydactyly syndrome (Table S3, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.27% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cranioectodermal dysplasia 2

Uncertain:1

Uncertain significance, 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, 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. -

Short-rib thoracic dysplasia 7 with or without polydactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 11, 2024

Variant summary: WDR35 c.1183A>T (p.Asn395Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251214 control chromosomes, predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in WDR35 causing WDR35-Related Disorders phenotype. c.1183A>T has been reported in the literature in individuals affected with short-rib polydactyly syndrome (Zhang_2018). These report(s) do not provide unequivocal conclusions about association of the variant with WDR35-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 288569). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T

Eigen

Benign

0.047

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

0.0081

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.9

D;N

REVEL

Benign

0.26

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

0.53

P;B

Vest4

0.49

MVP

0.83

MPC

0.29

ClinPred

0.039

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.37

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