rs1556909287

Positions:

• chrX-53534101-C-G

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.12928G>C​(p.Gly4310Arg) 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: 22)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.05

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 in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-53534101-C-G is Pathogenic according to our data. Variant chrX-53534101-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.12928G>C	p.Gly4310Arg	missense_variant	83/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.12928G>C	p.Gly4310Arg	missense_variant	83/84	1	NM_031407.7	ENSP00000262854	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

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

Pathogenic, criteria provided, single submitter	literature only	Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital	Jan 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2021	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2021

Western blotting demonstrated that HUWE1 protein level in the lymphorblastoid cells derived from a male patient carrying G4310R were significantly reduced compared to cells from a healthy relative (Friez et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33948573, 27535533, 27130160, 29307790, 29118367, 29180823) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.41	.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.7	.;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	.;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		0.96		.;Gain of methylation at K4305 (P = 0.0538);Gain of methylation at K4305 (P = 0.0538);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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: rs1556909287; hg19: chrX-53561062;