rs1556955128

Variant names:

• chrX-53573795-A-C
• rs1556955128
• NM_031407.7:c.6267T>G

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.6267T>G​(p.Ile2089Met) 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: 23)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.51
• 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-53573795-A-C is Pathogenic according to our data. Variant chrX-53573795-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375716.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.6267T>G	p.Ile2089Met	missense_variant	Exon 47 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.6267T>G	p.Ile2089Met	missense_variant	Exon 47 of 84	1	NM_031407.7	ENSP00000262854.6
HUWE1	ENST00000342160.7	c.6267T>G	p.Ile2089Met	missense_variant	Exon 46 of 83	5		ENSP00000340648.3
HUWE1	ENST00000612484.4	c.6240T>G	p.Ile2080Met	missense_variant	Exon 44 of 81	5		ENSP00000479451.1
HUWE1	ENST00000704099.1	c.6264T>G	p.Ile2088Met	missense_variant	Exon 46 of 83			ENSP00000515693.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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	0.80
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	.;L;L
PhyloP100		2.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.98	.;D;D
Vest4		0.88
MutPred		0.41		.;Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.81
MPC		2.1
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.52
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1556955128; hg19: chrX-53600755;