rs34169020

Positions:

• chr2-19975551-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000281405.9(WDR35):​c.549C>T​(p.Tyr183=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0359 in 1,612,960 control chromosomes in the GnomAD database, including 2,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (227 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1824 hom.)
• Consequence: WDR35 ENST00000281405.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.43

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-19975551-G-A is Benign according to our data. Variant chr2-19975551-G-A is described in ClinVar as [Benign]. Clinvar id is 333404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-19975551-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.549C>T	p.Tyr183=	synonymous_variant	6/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.549C>T	p.Tyr183=	synonymous_variant	6/27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8	c.549C>T	p.Tyr183=	synonymous_variant	6/28	1	NM_001006657.2	ENSP00000314444	A1
WDR35	ENST00000281405.9	c.549C>T	p.Tyr183=	synonymous_variant	6/27	1	NM_020779.4	ENSP00000281405	P3
WDR35	ENST00000414212.5	c.549C>T	p.Tyr183=	synonymous_variant, NMD_transcript_variant	6/28	5		ENSP00000390802
WDR35	ENST00000445063.5	c.87C>T	p.Tyr29=	synonymous_variant, NMD_transcript_variant	1/18	2		ENSP00000390105

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5838 AN: 152036 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0442 AC: 11061 AN: 250412 Hom.: 508 AF XY: 0.0420 AC XY: 5688 AN XY: 135378

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.194

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0420

GnomAD4 exome AF: 0.0357 AC: 52080 AN: 1460806 Hom.: 1824 Cov.: 31 AF XY: 0.0352 AC XY: 25590 AN XY: 726698

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0710

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0415

GnomAD4 genome AF: 0.0385 AC: 5855 AN: 152154 Hom.: 227 Cov.: 32 AF XY: 0.0392 AC XY: 2912 AN XY: 74374

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.0252

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0330 Hom.: 50

Bravo AF: 0.0428

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0295

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.4
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs34169020; hg19: chr2-20175312; COSMIC: COSV55602965;