2-19975596-A-T

Position:

chr2-19975596-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The ENST00000281405.9(WDR35):c.504T>A(p.Ser168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,012 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

WDR35
ENST00000281405.9 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.64

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

PP5

Variant 2-19975596-A-T is Pathogenic according to our data. Variant chr2-19975596-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1480830.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2 linkuse as main transcript	c.504T>A	p.Ser168Arg	missense_variant	6/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4 linkuse as main transcript	c.504T>A	p.Ser168Arg	missense_variant	6/27	ENST00000281405.9	NP_065830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 linkuse as main transcript	c.504T>A	p.Ser168Arg	missense_variant	6/28	1	NM_001006657.2	ENSP00000314444	A1	Q9P2L0-1
WDR35	ENST00000281405.9 linkuse as main transcript	c.504T>A	p.Ser168Arg	missense_variant	6/27	1	NM_020779.4	ENSP00000281405	P3	Q9P2L0-2
WDR35	ENST00000414212.5 linkuse as main transcript	c.504T>A	p.Ser168Arg	missense_variant, NMD_transcript_variant	6/28	5		ENSP00000390802
WDR35	ENST00000445063.5 linkuse as main transcript	c.42T>A	p.Ser14Arg	missense_variant, NMD_transcript_variant	1/18	2		ENSP00000390105

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has been observed in individual(s) with clinical features of a WDR35-related condition (PMID: 22486404; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 168 of the WDR35 protein (p.Ser168Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.092

T;T

Polyphen

0.32

B;B

Vest4

0.94

MutPred

0.65

Gain of MoRF binding (P = 0.0633);Gain of MoRF binding (P = 0.0633);

MVP

0.38

MPC

0.15

ClinPred

0.94

GERP RS

1.0

Varity_R

0.79

gMVP

0.84

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