NM_001099737.3:c.-156-83_-156-74delCCTGAGACAG

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_001099737.3(WDR83):​c.-156-83_-156-74delCCTGAGACAG variant causes a 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

WDR83
NM_001099737.3 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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
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
WDR83NM_001099737.3 linkc.-156-83_-156-74delCCTGAGACAG intron_variant Intron 1 of 10 ENST00000418543.8 NP_001093207.1 Q9BRX9
WDR83OSNM_016145.4 linkc.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
WDR83NR_029375.2 linkn.187-83_187-74delCCTGAGACAG intron_variant Intron 1 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WDR83ENST00000418543.8 linkc.-156-83_-156-74delCCTGAGACAG intron_variant Intron 1 of 10 1 NM_001099737.3 ENSP00000402653.3 Q9BRX9
WDR83OSENST00000596731.7 linkc.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
ENSG00000269590ENST00000597961.1 linkc.150+699_150+708delTCAGGCTGTC intron_variant Intron 2 of 4 4 ENSP00000472710.1 M0R2P5
ENSG00000285589ENST00000648033.1 linkn.*4189-4_*4194delTCAGGCTGTC splice_region_variant, non_coding_transcript_exon_variant Exon 14 of 14 ENSP00000498000.1 A0A3B3IU31
ENSG00000285589ENST00000648033.1 linkn.*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.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461272
Hom.:
0
AF XY:
0.00
AC XY:
0
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.:
32
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.

Other links and lift over

dbSNP: rs2024315415; hg19: chr19-12779233; API