chr14-102197836-G-GTAAC

Position:

• chr14-102197836-G-GTAAC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000322340.9(WDR20):​c.516_519dup​(p.Val174AsnfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR20 ENST00000322340.9 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

Genes affected

WDR20 (HGNC:19667): (WD repeat domain 20) This gene encodes a WD repeat-containing protein that functions to preserve and regulate the activity of the USP12-UAF1 deubiquitinating enzyme complex. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.126 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR20	NM_144574.4	c.432+2718_432+2721dup		intron_variant		ENST00000342702.8	NP_653175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR20	ENST00000342702.8	c.432+2718_432+2721dup		intron_variant		1	NM_144574.4	ENSP00000341037

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dolichocephaly;C0454644:Delayed speech and language development;C0557874:Global developmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Human Genetics Section, Sidra Medicine

Jul 11, 2024

A de novo mutation in an affected male with multiple congenital anomalies (list of phenotypes observed is under observations) and was absent from large population studies. Variant of uncertain significance (VUS) curated from https://franklin.genoox.com/clinical-db/variant/snp/chr14-102664173-G-GTAAC and Varsome. Clarification (23, July, 2024): Franklin and Varsome were utilized as supplementary tools; however, the patient exhibited a combination of phenotypes (see cases). Consequently, Whole Genome Sequencing (WGS) was performed, which identified the variant responsible for explaining the observed phenotypes. We are currently preparing the publication detailing these findings, and the PubMed ID (PMID) will be provided upon its release. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-102664173;