rs200649783

chr2-19969556-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001006657.2(WDR35):c.932G>T(p.Trp311Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

WDR35
NM_001006657.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.86

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 2-19969556-C-A is Pathogenic according to our data. Variant chr2-19969556-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446644.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr2-19969556-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2 linkuse as main transcript	c.932G>T	p.Trp311Leu	missense_variant	9/28	ENST00000345530.8
WDR35	NM_020779.4 linkuse as main transcript	c.932G>T	p.Trp311Leu	missense_variant	9/27	ENST00000281405.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000345530.8 linkuse as main transcript	c.932G>T	p.Trp311Leu	missense_variant	9/28	1	NM_001006657.2	A1	Q9P2L0-1
WDR35	ENST00000281405.9 linkuse as main transcript	c.932G>T	p.Trp311Leu	missense_variant	9/27	1	NM_020779.4	P3	Q9P2L0-2
WDR35	ENST00000414212.5 linkuse as main transcript	c.932G>T	p.Trp311Leu	missense_variant, NMD_transcript_variant	9/28	5
WDR35	ENST00000445063.5 linkuse as main transcript	c.470G>T	p.Trp157Leu	missense_variant, NMD_transcript_variant	4/18	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251262

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.0000432

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000838

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2

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

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	Observed with another WDR35 variant in two unrelated patients in published literature with skeletal ciliopathies and one patient with nephronophthisis, retinitis pigmentosa, liver cirrhosis and autism, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Duran et al., 2017; Zhang et al., 2018; Stokman et al., 2018); Reported as a single heterozygous variant in a patient in published literature with short-rib polydactyly syndrome who also had a heterozygous variant in the INTU gene inherited from the other parent; the authors suggested this may represent digenic inheritance (Toriyama et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29068549, 28400947, 27158779, 29974258) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 03, 2020	The WDR35 c.932G>T; p.Trp311Leu variant (rs200649783) is reported in the literature in the compound heterozygous state in individuals affected with short-rib polydactyly syndrome (Toriyama 2016, Zhang 2018). This variant is reported in ClinVar (Variation ID: 446644), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tryptophan at codon 311 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Toriyama M et al. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet. 2016 Jun;48(6):648-56. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -

Short-rib thoracic dysplasia 7/20 with polydactyly, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 02, 2018

- -

Cranioectodermal dysplasia 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

- -

Short-rib thoracic dysplasia 7 with or without polydactyly

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Oct 15, 2018

This variant is interpreted as Likely Pathogenic, for Short-rib thoracic dysplasia 7 with or without polydactyly, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/27158779) (https://www.ncbi.nlm.nih.gov/pubmed/28400947). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/28400947). -

SHORT-RIB THORACIC DYSPLASIA 7 WITHOUT POLYDACTYLY

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 02, 2018

- -

Short rib-polydactyly syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Mar 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-13

D;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.78

Loss of catalytic residue at L309 (P = 0.0062);Loss of catalytic residue at L309 (P = 0.0062);

MVP

0.89

MPC

0.74

ClinPred

1.0

GERP RS

4.6

Varity_R

0.94

gMVP

0.74

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