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rs397515334

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001006657.2(WDR35):​c.2891del​(p.Pro964LeufsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

WDR35
NM_001006657.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.71
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-19931374-AG-A is Pathogenic according to our data. Variant chr2-19931374-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 22.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-19931374-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WDR35NM_001006657.2 linkuse as main transcriptc.2891del p.Pro964LeufsTer15 frameshift_variant 25/28 ENST00000345530.8
WDR35NM_020779.4 linkuse as main transcriptc.2858del p.Pro953LeufsTer15 frameshift_variant 24/27 ENST00000281405.9
WDR35XM_011533007.3 linkuse as main transcriptc.1586del p.Pro529LeufsTer15 frameshift_variant 14/17
WDR35XR_426989.4 linkuse as main transcriptn.2848del non_coding_transcript_exon_variant 24/25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WDR35ENST00000345530.8 linkuse as main transcriptc.2891del p.Pro964LeufsTer15 frameshift_variant 25/281 NM_001006657.2 A1Q9P2L0-1
WDR35ENST00000281405.9 linkuse as main transcriptc.2858del p.Pro953LeufsTer15 frameshift_variant 24/271 NM_020779.4 P3Q9P2L0-2
WDR35ENST00000414212.5 linkuse as main transcriptc.*173del 3_prime_UTR_variant, NMD_transcript_variant 25/285
WDR35ENST00000445063.5 linkuse as main transcriptc.*1306del 3_prime_UTR_variant, NMD_transcript_variant 16/182

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251306
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135828
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:
0.00000342
AC:
5
AN:
1461230
Hom.:
0
Cov.:
41
AF XY:
0.00000138
AC XY:
1
AN XY:
726944
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Cranioectodermal dysplasia 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 10, 2010- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs397515334; hg19: chr2-20131135; API