19-12669353-C-A

Variant names:

• chr19-12669353-C-A
• NM_001099737.3:c.-36-402C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_016145.4(WDR83OS):​c.50+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR83OS NM_016145.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12669353-C-A is Pathogenic according to our data. Variant chr19-12669353-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3336829.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.-36-402C>A		intron_variant	Intron 2 of 10	ENST00000418543.8	NP_001093207.1
WDR83OS	NM_016145.4	c.50+1G>T		splice_donor_variant, intron_variant	Intron 1 of 3	ENST00000596731.7	NP_057229.1
WDR83	NR_029375.2	n.307-402C>A		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR83	ENST00000418543.8	c.-36-402C>A		intron_variant	Intron 2 of 10	1	NM_001099737.3	ENSP00000402653.3
WDR83OS	ENST00000596731.7	c.50+1G>T		splice_donor_variant, intron_variant	Intron 1 of 3	1	NM_016145.4	ENSP00000468969.1
ENSG00000269590	ENST00000597961.1	c.44+1G>T		splice_donor_variant, intron_variant	Intron 1 of 4	4		ENSP00000472710.1
ENSG00000285589	ENST00000648033.1	n.*3984+1G>T		splice_donor_variant, intron_variant	Intron 11 of 13			ENSP00000498000.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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 Turkish individual with neurodevelopmental delay. The variant is absent in gnomAD. In vivo studies in zebrafish suggest wdr83os loss of function is responsible for the human phenotype observed. Other variants in this gene were identified in association with neurodevelopmental delay and hypercholanemia, although bile salt measurements were not available for this patient/variant. -

Neurodevelopmental disorder with variable familial hypercholanemia Pathogenic:1

Nov 25, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.82	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: 2
DS_DL_spliceai		0.99		Position offset: 1

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: chr19-12780167;