rs202196322

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015910.7(WDPCP):c.176T>A(p.Ile59Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,596,126 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 9 hom. )

Consequence

WDPCP
NM_015910.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 3.64

Variant links:

Genes affected

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WDPCP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019254684).

BP6

Variant 2-63487479-A-T is Benign according to our data. Variant chr2-63487479-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220911.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr2-63487479-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (232/152132) while in subpopulation NFE AF= 0.00278 (189/67964). AF 95% confidence interval is 0.00246. There are 2 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDPCP	NM_015910.7 linkuse as main transcript	c.176T>A	p.Ile59Asn	missense_variant	3/18	ENST00000272321.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDPCP	ENST00000272321.12 linkuse as main transcript	c.176T>A	p.Ile59Asn	missense_variant	3/18	1	NM_015910.7	P1	O95876-1

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

232

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000788

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00136

AC:

338

AN:

248120

Hom.:

AF XY:

0.00131

AC XY:

177

AN XY:

134736

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.000760

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000984

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00258

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00224

AC:

3240

AN:

1443994

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1559

AN XY:

719468

show subpopulations

Gnomad4 AFR exome

AF:

0.000424

Gnomad4 AMR exome

AF:

0.000787

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000245

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00158

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152132

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000786

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00278

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00247

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.00263

EpiControl

AF:

0.00220

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	WDPCP: BS2 -

Bardet-Biedl syndrome 15

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. -

Heart defect - tongue hamartoma - polysyndactyly syndrome;C3150127:Bardet-Biedl syndrome 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

WDPCP-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bardet-Biedl syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.0070

T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

N;N;D

REVEL

Benign

0.25

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.0060

D;D;.

Polyphen

0.63

P;P;.

Vest4

0.86

MVP

0.78

MPC

0.37

ClinPred

0.031

GERP RS

3.1

Varity_R

0.33

gMVP

0.39

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