rs1557036768

chrX-53647390-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_031407.7(HUWE1):c.329G>A(p.Arg110Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110W) has been classified as Likely 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.38

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-53647391-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379239.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.
• PP2: Missense variant where missense usually causes diseases, HUWE1
• 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	UniProt
HUWE1	NM_031407.7	c.329G>A	p.Arg110Gln	missense_variant	6/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.329G>A	p.Arg110Gln	missense_variant	6/84	1	NM_031407.7	P2

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

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2022	Variant 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, criteria provided, single submitter	clinical testing	Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital	Jan 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Mar 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Sep 04, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	This 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	Not 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; This variant is associated with the following publications: (PMID: 32336296, 29180823, 29307790, 25985138) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2020

The 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
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
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
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

Other links and lift over

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