rs886041876

chrX-53551078-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_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. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 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 id is 841299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, HUWE1
• 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 [Likely_pathogenic]. Clinvar id is 280723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.9208C>T	p.Arg3070Cys	missense_variant	65/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.9208C>T	p.Arg3070Cys	missense_variant	65/84	1	NM_031407.7	P2
HUWE1	ENST00000342160.7	c.9208C>T	p.Arg3070Cys	missense_variant	64/83	5		P2
HUWE1	ENST00000612484.4	c.9181C>T	p.Arg3061Cys	missense_variant	62/81	5		A2
HUWE1	ENST00000704099.1	c.9205C>T	p.Arg3069Cys	missense_variant	64/83

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital	Jan 18, 2017	- -
Pathogenic, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 21, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 280723). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Statistical Genetics, Columbia University

Oct 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	28
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	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	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.95
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs886041876; hg19: chrX-53578039; COSMIC: COSV53358976; COSMIC: COSV53358976;