chr2-19933469-C-T

Position:

chr2-19933469-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_020779.4(WDR35):c.2590G>A(p.Ala864Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,798 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

WDR35
NM_020779.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.57

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:

WDR35 (HGNC:):

WDR35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 2-19933469-C-T is Pathogenic according to our data. Variant chr2-19933469-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 23.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-19933469-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2 linkuse as main transcript	c.2623G>A	p.Ala875Thr	missense_variant	23/28	ENST00000345530.8	NP_001006658.1	Q9P2L0-1
WDR35	NM_020779.4 linkuse as main transcript	c.2590G>A	p.Ala864Thr	missense_variant	22/27	ENST00000281405.9	NP_065830.2	Q9P2L0-2
WDR35	XM_011533007.3 linkuse as main transcript	c.1318G>A	p.Ala440Thr	missense_variant	12/17		XP_011531309.1
WDR35	XR_426989.4 linkuse as main transcript	n.2680G>A		non_coding_transcript_exon_variant	22/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8 linkuse as main transcript	c.2623G>A	p.Ala875Thr	missense_variant	23/28	1	NM_001006657.2	ENSP00000314444.5		Q9P2L0-1
WDR35	ENST00000281405.9 linkuse as main transcript	c.2590G>A	p.Ala864Thr	missense_variant	22/27	1	NM_020779.4	ENSP00000281405.5		Q9P2L0-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251254

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727128

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 25, 2017

The p.Ala875Thr variant was previously reported in trans with another WDR35 variant, c.2891del; p.Pro964fs, identified by whole exome analysis in a child with Sensenbrenner syndrome also known as cranioectodermal dysplasia (Gilissen 2010). At nine years of age that patient had small thorax, pectus excavatum, rhizomelic shortening of limbs, short and broad hands, bilateral sandal gap between first and second toe, hypertelorism, low-set simple ears and thin hair (Gilissen 2010). Additionally, functional in vitro study showed that p.Ala875Thr variant impaired IFT-A-mediated cargo transport to cilia (Fu 2016). The p.Ala875Thr variant (rs267607175) is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in ClinVar (Variation ID 23) and it is listed in the Genome Aggregation Consortium (gnomAD) browser with an overall allele frequency of 0.0004 percent (identified on 1 European chromosome out of all 246,026 analyzed chromosomes). Alanine 875 is highly conserved considering 11 species (Alamut software v2.9.0) but computational programs predict mixed effect of this variant on the protein (SIFT: tolerated, PolyPhen-2: probably damaging and MutationTaster: disease causing). -

Cranioectodermal dysplasia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 10, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.035

MutationAssessor

Pathogenic

3.4

.;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.69

.;Gain of helix (P = 0.062);

MVP

0.64

MPC

0.54

ClinPred

1.0

GERP RS

5.3

Varity_R

0.67

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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