rs267607174

chr2-19945787-T-C

Variant summary

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

The NM_001006657.2(WDR35):c.1877A>G(p.Glu626Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR35 NM_001006657.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.02

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-19945787-T-C is Pathogenic according to our data. Variant chr2-19945787-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 21.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2	c.1877A>G	p.Glu626Gly	missense_variant, splice_region_variant	17/28	ENST00000345530.8
WDR35	NM_020779.4	c.1844A>G	p.Glu615Gly	missense_variant, splice_region_variant	16/27	ENST00000281405.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000345530.8	c.1877A>G	p.Glu626Gly	missense_variant, splice_region_variant	17/28	1	NM_001006657.2	A1
WDR35	ENST00000281405.9	c.1844A>G	p.Glu615Gly	missense_variant, splice_region_variant	16/27	1	NM_020779.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727060

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cranioectodermal dysplasia 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.77
MutPred		0.52		.;Loss of sheet (P = 0.0181);.;
MVP		0.78
MPC		0.59
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 27
DS_DL_spliceai		0.87		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607174; hg19: chr2-20145548;