rs886041876

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_031407.7(HUWE1):c.9208C>T(p.Arg3070Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3070H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.09

Publications

7 publications found

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]

HUWE1 Gene-Disease associations (from GenCC):

intellectual disability, X-linked syndromic, Turner type
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HUWE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-53551077-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 841299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant X-53551078-G-A is Pathogenic according to our data. Variant chrX-53551078-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.9208C>T	p.Arg3070Cys	missense_variant	Exon 65 of 84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HUWE1	ENST00000262854.11 link	c.9208C>T	p.Arg3070Cys	missense_variant	Exon 65 of 84	1	NM_031407.7	ENSP00000262854.6	Q7Z6Z7-1
HUWE1	ENST00000342160.7 link	c.9208C>T	p.Arg3070Cys	missense_variant	Exon 64 of 83	5		ENSP00000340648.3	Q7Z6Z7-1
HUWE1	ENST00000612484.4 link	c.9181C>T	p.Arg3061Cys	missense_variant	Exon 62 of 81	5		ENSP00000479451.1	Q7Z6Z7-3
HUWE1	ENST00000704099.1 link	c.9205C>T	p.Arg3069Cys	missense_variant	Exon 64 of 83			ENSP00000515693.1	A0A994J483

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type

Pathogenic:6

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280723). A different missense change at the same codon (p.Arg3070His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000841299). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2017

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jun 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3070 of the HUWE1 protein (p.Arg3070Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HUWE1-related disease (PMID: 29180823). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280723). 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. -

Nov 10, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29180823, 32336296, 31130284, 33710394, 33504798) -

Neurodevelopmental delay

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Dec 16, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.9208C>T (p.R3070C) alteration is located in exon 65 (coding exon 62) of the HUWE1 gene. This alteration results from a C to T substitution at nucleotide position 9208, causing the arginine (R) at amino acid position 3070 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in both heterozygous female and hemizygous male individual(s) with features consistent with HUWE1-related neurodevelopmental disorder; in at least one individual, it was determined to be a de novo variant (Moortgat, 2018; Monies, 2019; Järvelä, 2021; Zhou, 2022; Schmidt, 2024). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Intellectual disability

Pathogenic:1

Oct 16, 2020

Center for Statistical Genetics, Columbia University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;D;D

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.5

.;H;H

PhyloP100

9.1

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.5

.;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.84

MutPred

0.70

.;Loss of phosphorylation at S3072 (P = 0.09);Loss of phosphorylation at S3072 (P = 0.09);

MVP

0.98

MPC

2.3

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.95

gMVP

0.97

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over