rs121918526

Variant names:

• chrX-53551420-C-T
• rs121918526
• NM_031407.7:c.8942G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2981L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.14
• Publications: 18 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 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-53551420-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4278159.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 10677.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	c.8942G>A	p.Arg2981His	missense_variant	Exon 64 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.8942G>A	p.Arg2981His	missense_variant	Exon 64 of 84	1	NM_031407.7	ENSP00000262854.6
HUWE1	ENST00000342160.7	c.8942G>A	p.Arg2981His	missense_variant	Exon 63 of 83	5		ENSP00000340648.3
HUWE1	ENST00000612484.4	c.8915G>A	p.Arg2972His	missense_variant	Exon 61 of 81	5		ENSP00000479451.1
HUWE1	ENST00000704099.1	c.8939G>A	p.Arg2980His	missense_variant	Exon 63 of 83			ENSP00000515693.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.000119 Hom.: 0

ClinVar

Significance: Pathogenic/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

Mar 21, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as hemizygous._x000D_ Criteria applied: PS2_MOD, PS3_SUP, PS4_SUP, PM2_SUP, PP2, PP3 -

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 23871722, 18252223, 27130160, 19377476, 33057194, 35982159) -

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
DEOGEN2	Uncertain	0.78	.;D;D
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
MutationAssessor	Pathogenic	3.6	.;H;H
PhyloP100		7.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	.;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;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
Mutation Taster		=57/43	disease causing (ClinVar)

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

Other links and lift over

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