19-12668419-GGACAGCCTGA-G

Variant names:

• chr19-12668419-GGACAGCCTGA-G
• rs2024315415
• NM_001099737.3:c.-156-83_-156-74delCCTGAGACAG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.75

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]

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]

ENSG00000269590 (HGNC:):

ACMG classification

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	c.-156-83_-156-74delCCTGAGACAG		intron_variant	Intron 1 of 10	ENST00000418543.8	NP_001093207.1
WDR83OS	NM_016145.4	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
WDR83	NR_029375.2	n.187-83_187-74delCCTGAGACAG		intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR83	ENST00000418543.8	c.-156-83_-156-74delCCTGAGACAG		intron_variant	Intron 1 of 10	1	NM_001099737.3	ENSP00000402653.3
WDR83OS	ENST00000596731.7	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
ENSG00000269590	ENST00000597961.1	c.150+699_150+708delTCAGGCTGTC		intron_variant	Intron 2 of 4	4		ENSP00000472710.1
ENSG00000285589	ENST00000648033.1	n.*4189-4_*4194delTCAGGCTGTC		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*4189-4_*4194delTCAGGCTGTC		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 14 of 14			ENSP00000498000.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461272 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726864

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2024315415; hg19: chr19-12779233;