Variant 19-12668419-GGACAGCCTGA-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_016145.4(WDR83OS):c.255-4_260delTCAGGCTGTC(p.Met85_Ser87delinsIle) variant causes a splice acceptor, disruptive inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

WDR83OS
NM_016145.4 splice_acceptor, disruptive_inframe_deletion, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.75

Variant links:

Genes affected

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

WDR83 links:

WDR83OS (HGNC:30203): (WD repeat domain 83 opposite strand) Enables protein folding chaperone. Involved in protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

WDR83OS links:

ENSG00000269590 (HGNC:):

ENSG00000269590 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 0.20560747663551404 fraction of the gene.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-12668419-GGACAGCCTGA-G is Pathogenic according to our data. Variant chr19-12668419-GGACAGCCTGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 2577971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR83	NM_001099737.3 link	c.-156-83_-156-74delCCTGAGACAG		intron_variant	Intron 1 of 10	ENST00000418543.8	NP_001093207.1	Q9BRX9
WDR83OS	NM_016145.4 link	c.255-4_260delTCAGGCTGTC	p.Met85_Ser87delinsIle	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 4 of 4	ENST00000596731.7	NP_057229.1	Q9Y284
WDR83	NR_029375.2 link	n.187-83_187-74delCCTGAGACAG		intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WDR83	ENST00000418543.8 link	c.-156-83_-156-74delCCTGAGACAG		intron_variant	Intron 1 of 10	1	NM_001099737.3	ENSP00000402653.3	Q9BRX9
WDR83OS	ENST00000596731.7 link	c.255-4_260delTCAGGCTGTC	p.Met85_Ser87delinsIle	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 4 of 4	1	NM_016145.4	ENSP00000468969.1	Q9Y284
ENSG00000269590	ENST00000597961.1 link	c.150+699_150+708delTCAGGCTGTC		intron_variant	Intron 2 of 4	4		ENSP00000472710.1	M0R2P5
ENSG00000285589	ENST00000648033.1 link	n.4189-4_4194delTCAGGCTGTC		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000498000.1	A0A3B3IU31
ENSG00000285589	ENST00000648033.1 link	n.4189-4_4194delTCAGGCTGTC		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 14 of 14			ENSP00000498000.1	A0A3B3IU31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461272

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726864

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholanemia, familial

Pathogenic:1

Aug 13, 2024

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as homozygous in one individual with neurodevelopmental delay and hypercholanemia. The variant is absent in gnomAD. In vivo studies in zebrafish suggest wdr83os loss of function is responsible for the human phenotype observed. -

not provided

Pathogenic:1

Oct 14, 2020

Molecular Genetics laboratory, Necker Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over