rs121918526

Positions:

• chrX-53551420-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_031407.7(HUWE1):​c.8942G>A​(p.Arg2981His) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.14

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
• PP2: Missense variant where missense usually causes diseases, HUWE1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant X-53551420-C-T is Pathogenic according to our data. Variant chrX-53551420-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53551420-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.8942G>A	p.Arg2981His	missense_variant	64/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.8942G>A	p.Arg2981His	missense_variant	64/84	1	NM_031407.7	P2
HUWE1	ENST00000342160.7	c.8942G>A	p.Arg2981His	missense_variant	63/83	5		P2
HUWE1	ENST00000612484.4	c.8915G>A	p.Arg2972His	missense_variant	61/81	5		A2
HUWE1	ENST00000704099.1	c.8939G>A	p.Arg2980His	missense_variant	63/83

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00426 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 21, 2023	This variant was identified as hemizygous._x000D_ Criteria applied: PS2_MOD, PS3_SUP, PS4_SUP, PM2_SUP, PP2, PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2017

The R2981H variant in the HUWE1 gene was identified in three males from one family with severe to profound intellectual disability, but they underwent testing for only a small subset of genes (Froyen et al., 2008). The R2981H (reported as R2871H due to alternative nomenclature) was also identified in a single individual from a large cohort of X-linked intellectual disability families, but additional details about the individual's features or other variants also detected were not reported (Tarpey et al., 2009). The R2981H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2981H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R2981H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.87
MutPred		0.77		.;Loss of disorder (P = 0.0881);Loss of disorder (P = 0.0881);
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.99
gMVP		0.59

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: rs121918526; hg19: chrX-53578381; COSMIC: COSV53347951; COSMIC: COSV53347951;