rs1556910184

chrX-53534615-C-GchrX-53534615-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_031407.7(HUWE1):c.12732G>C(p.Glu4244Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.50

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HUWE1
• PP5: Variant X-53534615-C-G is Pathogenic according to our data. Variant chrX-53534615-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375723.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.12732G>C	p.Glu4244Asp	missense_variant	82/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.12732G>C	p.Glu4244Asp	missense_variant	82/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Benign	0.89
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.037	D;D;D
Polyphen		0.90	.;P;P
Vest4		0.54
MutPred		0.48		.;Gain of relative solvent accessibility (P = 0.1894);Gain of relative solvent accessibility (P = 0.1894);
MVP		0.84
MPC		1.3
ClinPred		0.94	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.91

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: rs1556910184; hg19: chrX-53561576;