rs199952377

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001006657.2(WDR35):c.1922T>G(p.Leu641*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,573,428 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

WDR35
NM_001006657.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.99

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

cranioectodermal dysplasia 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, ClinGen, Ambry Genetics
short-rib thoracic dysplasia 7 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR35 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-19941796-A-C is Pathogenic according to our data. Variant chr2-19941796-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR35	NM_001006657.2 link	c.1922T>G	p.Leu641*	stop_gained	Exon 18 of 28	ENST00000345530.8	NP_001006658.1	Q9P2L0-1
WDR35	NM_020779.4 link	c.1889T>G	p.Leu630*	stop_gained	Exon 17 of 27	ENST00000281405.9	NP_065830.2	Q9P2L0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 link	c.1922T>G	p.Leu641*	stop_gained	Exon 18 of 28	1	NM_001006657.2	ENSP00000314444.5		Q9P2L0-1
WDR35	ENST00000281405.9 link	c.1889T>G	p.Leu630*	stop_gained	Exon 17 of 27	1	NM_020779.4	ENSP00000281405.5		Q9P2L0-2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000155

AC:

AN:

218956

AF XY:

0.000144

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 FIN exome

AF:

0.000198

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.000365

GnomAD4 exome

AF:

0.000107

AC:

152

AN:

1421198

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

704674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32918

American (AMR)

AF:

0.0000235

AC:

AN:

42504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.00

AC:

AN:

39132

South Asian (SAS)

AF:

0.00

AC:

AN:

83200

European-Finnish (FIN)

AF:

0.000314

AC:

AN:

50946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.000123

AC:

133

AN:

1083584

Other (OTH)

AF:

0.0000343

AC:

AN:

58332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000322

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000917

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 14, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34490615, 25914204, 28332779, 22486404, 31980526, 34426522, 31589614, 34421506, 38161384, 35875935, 29068549, 33421337, 37895316, 38792657) -

Oct 14, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WDR35: PVS1, PM2 -

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

Pathogenic:2

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu641*) in the WDR35 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR35 are known to be pathogenic (PMID: 22486404, 29068549). This variant is present in population databases (rs199952377, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with cranioectodermal dysplasia, also known as Sensenbrenner syndrome (PMID: 22486404, 25914204, 28332779). ClinVar contains an entry for this variant (Variation ID: 65619). For these reasons, this variant has been classified as Pathogenic. -

WDR35-related disorder

Pathogenic:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The WDR35 c.1922T>G (p.Leu641Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in two individuals with cranioectodermal dysplasia, both in a compound heterozygous state with a missense variant (Hoffer et al. 2013; Li et al. 2015). The variant was absent from 300 control chromosomes but is reported at a frequency of 0.00039 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Leu641Ter variant is classified as likely pathogenic for WDR35-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 25, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: WDR35 c.1922T>G (p.Leu641X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 218956 control chromosomes. c.1922T>G has been reported in the literature in individuals affected with WDR35-Related Disorders (Li_2015). These data do not allow any conclusion about variant significance. 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: 25914204). ClinVar contains an entry for this variant (Variation ID: 65619). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cranioectodermal dysplasia 2

Pathogenic:2

Mar 30, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 26, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jeune thoracic dystrophy

Pathogenic:2

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Cranioectodermal dysplasia

Pathogenic:1

Mar 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Leu641X variant in WDR35 has been reported in 3 compound heterozygous indi viduals with cranioectodermal dysplasia (Hoffer 2013, Li 2015, Walczak-Sztulpa 2 017) and has been reported in ClinVar (Variation ID #65619). This variant has al so been identified in 0.035% (37/105,800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs19995237 7). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsens e variant leads to a premature termination codon at position 641 which is predic ted to lead to a truncated or absent protein. In summary, although additional st udies are required to fully establish its clinical significance, the p.Leu641X variant is likely pathogenic for cranioectodermal dysplasia in an autosomal rece ssive manner. ACMG/AMP Criteria applied: PVS1_Strong, PS3_Supporting, PM3_Suppor ting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.0

Vest4

0.60

GERP RS

5.6

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over