rs1556912828

Positions:

• chrX-53536209-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_031407.7(HUWE1):​c.12469C>G​(p.Leu4157Val) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.78

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 12 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, 0.826
• PP5: Variant X-53536209-G-C is Pathogenic according to our data. Variant chrX-53536209-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375722.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.12469C>G	p.Leu4157Val	missense_variant	80/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.12469C>G	p.Leu4157Val	missense_variant	80/84	1	NM_031407.7	ENSP00000262854	P2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2020

- -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Intellectual disability, X-linked syndromic, Turner type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital

Jan 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.62
DEOGEN2	Benign	0.37	.;T;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.7	.;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	.;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.0010	.;B;B
Vest4		0.80
MutPred		0.64		.;Gain of catalytic residue at L4157 (P = 0.0648);Gain of catalytic residue at L4157 (P = 0.0648);
MVP		0.92
MPC		1.4
ClinPred		0.95	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.76
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1556912828; hg19: chrX-53563170;