rs1553313859

Positions:

• chr2-19913645-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_020779.4(WDR35):​c.3426G>T​(p.Trp1142Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR35 NM_020779.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.49

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 2-19913645-C-A is Pathogenic according to our data. Variant chr2-19913645-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 488657.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.3459G>T	p.Trp1153Cys	missense_variant	28/28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.3426G>T	p.Trp1142Cys	missense_variant	27/27	ENST00000281405.9	NP_065830.2
WDR35	XM_011533007.3	c.2154G>T	p.Trp718Cys	missense_variant	17/17		XP_011531309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8	c.3459G>T	p.Trp1153Cys	missense_variant	28/28	1	NM_001006657.2	ENSP00000314444.5
WDR35	ENST00000281405.9	c.3426G>T	p.Trp1142Cys	missense_variant	27/27	1	NM_020779.4	ENSP00000281405.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cranioectodermal dysplasia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Benign	0.18	.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-9.0	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.71		.;Gain of glycosylation at T1148 (P = 0.1295);
MVP		0.82
MPC		0.70
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553313859; hg19: chr2-20113406; COSMIC: COSV99853590;