rs143343508

chr2-19966735-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001006657.2(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. 12/20 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 NM_001006657.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 4.93

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014500916).
• 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152196 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00194 AC XY: 263 AN XY: 135800

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.: 4 Cov.: 31 AF XY: 0.00253 AC XY: 1836 AN XY: 727046

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.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74482

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.: 0

Bravo AF: 0.00127

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

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:1 Uncertain: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	-	- -

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

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. -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	0.0081	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs143343508; hg19: chr2-20166496; COSMIC: COSV99853624;