rs121918526
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_031407.7(HUWE1):c.8942G>A(p.Arg2981His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
HUWE1
NM_031407.7 missense
NM_031407.7 missense
Scores
8
3
1
Clinical Significance
Conservation
PhyloP100: 7.14
Genes affected
HUWE1 (HGNC:30892): (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HUWE1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
?
Variant X-53551420-C-T is Pathogenic according to our data. Variant chrX-53551420-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53551420-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HUWE1 | NM_031407.7 | c.8942G>A | p.Arg2981His | missense_variant | 64/84 | ENST00000262854.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HUWE1 | ENST00000262854.11 | c.8942G>A | p.Arg2981His | missense_variant | 64/84 | 1 | NM_031407.7 | P2 | |
HUWE1 | ENST00000342160.7 | c.8942G>A | p.Arg2981His | missense_variant | 63/83 | 5 | P2 | ||
HUWE1 | ENST00000612484.4 | c.8915G>A | p.Arg2972His | missense_variant | 61/81 | 5 | A2 | ||
HUWE1 | ENST00000704099.1 | c.8939G>A | p.Arg2980His | missense_variant | 63/83 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Alfa
AF:
Hom.:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, X-linked syndromic, Turner type Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 21, 2023 | This variant was identified as hemizygous._x000D_ Criteria applied: PS2_MOD, PS3_SUP, PS4_SUP, PM2_SUP, PP2, PP3 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2017 | The R2981H variant in the HUWE1 gene was identified in three males from one family with severe to profound intellectual disability, but they underwent testing for only a small subset of genes (Froyen et al., 2008). The R2981H (reported as R2871H due to alternative nomenclature) was also identified in a single individual from a large cohort of X-linked intellectual disability families, but additional details about the individual's features or other variants also detected were not reported (Tarpey et al., 2009). The R2981H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2981H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R2981H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
0.77
.;Loss of disorder (P = 0.0881);Loss of disorder (P = 0.0881);
MVP
MPC
2.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at