chrX-53534615-C-G

Variant names:

• chrX-53534615-C-G
• rs1556910184
• NM_031407.7:c.12732G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 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
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 375723.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.12732G>C	p.Glu4244Asp	missense_variant	Exon 82 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.12732G>C	p.Glu4244Asp	missense_variant	Exon 82 of 84	1	NM_031407.7	ENSP00000262854.6

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

Jan 18, 2017

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
DEOGEN2	Benign	0.35	.;T;T
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
MutationAssessor	Uncertain	2.6	.;M;M
PhyloP100		1.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.011	.;D;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
Mutation Taster		=2/98	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: rs1556910184; hg19: chrX-53561576;