chrX-53533365-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_031407.7(HUWE1):​c.13069C>T​(p.Arg4357Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,206,317 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

9
5
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.42
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]

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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;
PP2
Missense variant in the HUWE1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 8.8732 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUWE1NM_031407.7 linkc.13069C>T p.Arg4357Cys missense_variant Exon 84 of 84 ENST00000262854.11 NP_113584.3 Q7Z6Z7-1A0A024R9W5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HUWE1ENST00000262854.11 linkc.13069C>T p.Arg4357Cys missense_variant Exon 84 of 84 1 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1

Frequencies

GnomAD3 genomes
AF:
0.00000900
AC:
1
AN:
111116
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33316
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000956
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
9.13e-7
AC:
1
AN:
1095201
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
360631
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000900
AC:
1
AN:
111116
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000956
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 17, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4357 of the HUWE1 protein (p.Arg4357Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HUWE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1195142). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 01, 2021Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
HUWE1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 06, 2024The HUWE1 c.13069C>T variant is predicted to result in the amino acid substitution p.Arg4357Cys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Of note, a different substitution at the same codon, defined as c.13070G>A (p.Arg4357His), was reported in a newborn with syndromic presentation including blepharophimosis, sparse eyebrow, micrognathia, nystagmus, muscular, hypotonia of the trunk, broad hallux, clinodactyly of the 5th finger, primitive reflexes, and supernumerary nipple, but this individual also has a likely pathogenic variant in SOX11 (eTable 3, Lunke et al. 2020. PubMed ID: 32573669). At this time, the clinical significance of the c.13069C>T (p.Arg4357Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Benign
0.38
.;T;T
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;.;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Uncertain
0.099
D
MutationAssessor
Pathogenic
3.0
.;M;M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.2
.;D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.69
MutPred
0.67
.;Gain of ubiquitination at K4355 (P = 0.1079);Gain of ubiquitination at K4355 (P = 0.1079);
MVP
0.90
MPC
1.8
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs2060851157; hg19: chrX-53560326; COSMIC: COSV53356962; COSMIC: COSV53356962; API