WDR35 p.Leu641*

Variant names:

• chr2-19941763-A-C
• NM_001006657.2:c.1955T>G
• WDR35 p.Leu652*

Your query was ambiguous. Multiple possible variants found:

• chr2-19941763-A-C
• chr2-19941796-A-C
• chr2-19941763-A-T
• chr2-19941796-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020779.4(WDR35):​c.1922T>G​(p.Leu641*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR35 NM_020779.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.99
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020779.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	NM_001006657.2	MANE Plus Clinical	c.1955T>G	p.Leu652*	stop_gained	Exon 18 of 28	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.1922T>G	p.Leu641*	stop_gained	Exon 17 of 27	NP_065830.2	Q9P2L0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.1955T>G	p.Leu652*	stop_gained	Exon 18 of 28	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.1922T>G	p.Leu641*	stop_gained	Exon 17 of 27	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000453014.1	TSL:1	c.560T>G	p.Leu187*	stop_gained	Exon 6 of 10	ENSP00000404409.1	H0Y6C0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.0
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-20141524;