X-53534049-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5
The NM_031407.7(HUWE1):c.12980G>A(p.Arg4327Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,209,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )
Consequence
HUWE1
NM_031407.7 missense
NM_031407.7 missense
Scores
3
6
3
Clinical Significance
Conservation
PhyloP100: 7.00
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, HUWE1
PP5
Variant X-53534049-C-T is Pathogenic according to our data. Variant chrX-53534049-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1077131.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HUWE1 | NM_031407.7 | c.12980G>A | p.Arg4327Gln | missense_variant | 83/84 | ENST00000262854.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HUWE1 | ENST00000262854.11 | c.12980G>A | p.Arg4327Gln | missense_variant | 83/84 | 1 | NM_031407.7 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000179 AC: 2AN: 111755Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33931
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GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183506Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67936
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GnomAD4 exome AF: 0.00000182 AC: 2AN: 1097942Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 363298
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GnomAD4 genome AF: 0.0000179 AC: 2AN: 111755Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33931
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Abnormal corpus callosum morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics Institute, Tel Aviv Sourasky Medical Center | May 12, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35229910) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
0.53
.;Loss of ubiquitination at K4322 (P = 0.0949);Loss of ubiquitination at K4322 (P = 0.0949);
MVP
MPC
1.6
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at