rs199952377

Positions:

• chr2-19941796-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001006657.2(WDR35):​c.1922T>G​(p.Leu641Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-19941796-A-C is Pathogenic according to our data. Variant chr2-19941796-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-19941796-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.1922T>G	p.Leu641Ter	stop_gained	18/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.1889T>G	p.Leu630Ter	stop_gained	17/27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8	c.1922T>G	p.Leu641Ter	stop_gained	18/28	1	NM_001006657.2	ENSP00000314444	A1
WDR35	ENST00000281405.9	c.1889T>G	p.Leu630Ter	stop_gained	17/27	1	NM_020779.4	ENSP00000281405	P3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152230 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000155 AC: 34 AN: 218956 Hom.: 0 AF XY: 0.000144 AC XY: 17 AN XY: 117748

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: 0.000198

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.000365

GnomAD4 exome AF: 0.000107 AC: 152 AN: 1421198 Hom.: 0 Cov.: 28 AF XY: 0.000121 AC XY: 85 AN XY: 704674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000314

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.0000343

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000423 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000917 AC: 11

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	WDR35: PVS1, PS4:Moderate -

WDR35-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Cranioectodermal dysplasia 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 26, 2023	- -

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	- -

Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

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. -

Cranioectodermal dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 12, 2018

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	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.60
GERP RS		5.6

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

LitVar

Other links and lift over

dbSNP: rs199952377; hg19: chr2-20141557;