rs1557036768

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_031407.7(HUWE1):​c.329G>A​(p.Arg110Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

HUWE1
NM_031407.7 missense

Scores

9
7
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.38
Variant links:
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]

Genome browser will be placed here

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 in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant X-53647390-C-T is Pathogenic according to our data. Variant chrX-53647390-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53647390-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-53647390-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HUWE1NM_031407.7 linkuse as main transcriptc.329G>A p.Arg110Gln missense_variant 6/84 ENST00000262854.11 NP_113584.3 Q7Z6Z7-1A0A024R9W5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HUWE1ENST00000262854.11 linkuse as main transcriptc.329G>A p.Arg110Gln missense_variant 6/841 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1094191
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
359719
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:7
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 20, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Medical Genetics and Molecular Medicine, Haukeland University HospitalJan 18, 2017- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneAug 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 22, 2022Variant summary: HUWE1 c.329G>A (p.Arg110Gln) results in a conservative amino acid change located in a domain of unknown function DUF908 (IPR010309) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183017 control chromosomes (gnomAD). c.329G>A has been reported in the literature as a de novo variant in the heterozygous state in three female individuals affected with intellectual disability and craniosynostosis (e.g. Taylor_2015, Moortgat_2018). In all three cases, these individuals exhibited skewed X-inactivation of the wildtype X chromosome, resulting in preferential expression of the variant allele. These data indicate that the variant is likely associated with disease. Furthermore, a different missense change at the same amino acid, p.Arg110Trp, has been observed in at least one hemizygous male with similar clinical features (e.g. Taylor_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic HealthcareMar 23, 2018- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHSep 04, 2018- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 22, 2024Not observed at significant frequency in large population cohorts (gnomAD); 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: 29307790, 25985138, 36939041, 30797980, 32336296, 29180823, 37086723) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 17, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 110 of the HUWE1 protein (p.Arg110Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HUWE1-related conditions (PMID: 25985138, 29180823). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 375709). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HUWE1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 09, 2020The c.329G>A (p.R110Q) alteration is located in exon 6 (coding exon 3) of the HUWE1 gene. This alteration results from a G to A substitution at nucleotide position 329, causing the arginine (R) at amino acid position 110 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the HUWE1 c.329G>A alteration was not observed, with coverage at this position. This alteration was described as a recurrent de novo alteration in female patients with a neurodevelopmental syndrome that included motor delays, mild intellectual disability, skeletal anomalies, craniosynostosis, and facial dysmorphic features. All females showed skewed inactivation of the X chromosome favoring the affected allele (Taylor, 2015; Moortgat, 2018). The p.R110 amino acid is conserved in available vertebrate species. The p.R110Q alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
.;D;D
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;.;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
0.0089
D
MutationAssessor
Uncertain
2.7
M;M;M
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.3
.;D;D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.89
MutPred
0.94
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.98
MPC
2.2
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs1557036768; hg19: chrX-53674333; COSMIC: COSV53337343; COSMIC: COSV53337343; API