rs1191779

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001006657.2(WDR35):c.2857-14G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,612,746 control chromosomes in the GnomAD database, including 795,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71782 hom., cov: 31)

Exomes 𝑓: 1.0 ( 723524 hom. )

Consequence

WDR35
NM_001006657.2 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.09

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-19931423-C-A is Benign according to our data. Variant chr2-19931423-C-A is described in ClinVar as [Benign]. Clinvar id is 167846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-19931423-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
WDR35	NM_001006657.2 linkuse as main transcript	c.2857-14G>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000345530.8
WDR35	NM_020779.4 linkuse as main transcript	c.2824-14G>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000281405.9
WDR35	XM_011533007.3 linkuse as main transcript	c.1552-14G>T	splice_polypyrimidine_tract_variant, intron_variant
WDR35	XR_426989.4 linkuse as main transcript	n.2814-14G>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
WDR35	ENST00000281405.9 linkuse as main transcript	c.2824-14G>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_020779.4	P3	Q9P2L0-2
WDR35	ENST00000345530.8 linkuse as main transcript	c.2857-14G>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_001006657.2	A1	Q9P2L0-1
WDR35	ENST00000414212.5 linkuse as main transcript	c.*139-14G>T	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5
WDR35	ENST00000445063.5 linkuse as main transcript	c.*1272-14G>T	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.970

AC:

147581

AN:

152112

Hom.:

71734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.903

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.983

Gnomad ASJ

AF:

0.988

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.985

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.981

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.977

GnomAD3 exomes

AF:

0.990

AC:

248082

AN:

250652

Hom.:

122857

AF XY:

0.991

AC XY:

134376

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.899

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

0.991

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.985

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.990

GnomAD4 exome

AF:

0.995

AC:

1453574

AN:

1460518

Hom.:

723524

Cov.:

AF XY:

0.995

AC XY:

723044

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.901

Gnomad4 AMR exome

AF:

0.994

Gnomad4 ASJ exome

AF:

0.991

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.986

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.999

Gnomad4 OTH exome

AF:

0.989

GnomAD4 genome

AF:

0.970

AC:

147686

AN:

152228

Hom.:

71782

Cov.:

AF XY:

0.971

AC XY:

72248

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.903

Gnomad4 AMR

AF:

0.984

Gnomad4 ASJ

AF:

0.988

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.985

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.998

Gnomad4 OTH

AF:

0.977

Alfa

AF:

0.985

Hom.:

13569

Bravo

AF:

0.966

Asia WGS

AF:

0.984

AC:

3408

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cranioectodermal dysplasia 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.047

DANN

Benign

0.30

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