X-53537626-G-A

Variant names:

• chrX-53537626-G-A
• rs1556914274
• NM_031407.7:c.12067C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_031407.7(HUWE1):​c.12067C>T​(p.Arg4023Cys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 3.66
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant X-53537626-G-A is Pathogenic according to our data. Variant chrX-53537626-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375718.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031407.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	NM_031407.7	MANE Select	c.12067C>T	p.Arg4023Cys	missense	Exon 78 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.12067C>T	p.Arg4023Cys	missense	Exon 77 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.12064C>T	p.Arg4022Cys	missense	Exon 78 of 84	NP_001427980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	ENST00000262854.11	TSL:1 MANE Select	c.12067C>T	p.Arg4023Cys	missense	Exon 78 of 84	ENSP00000262854.6
	HUWE1	ENST00000342160.7	TSL:5	c.12067C>T	p.Arg4023Cys	missense	Exon 77 of 83	ENSP00000340648.3
	HUWE1	ENST00000612484.4	TSL:5	c.12040C>T	p.Arg4014Cys	missense	Exon 75 of 81	ENSP00000479451.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:3

Mar 29, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Jun 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HUWE1: PM2, PS4:Moderate, PP2, PP3, PP4

Mar 13, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29180823, 36111624, 36307859, 31957018, 36353900)

Inborn genetic diseases Uncertain:1

Jun 27, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R4023C variant (also known as c.12067C>T), located in coding exon 75 of the HUWE1 gene, results from a C to T substitution at nucleotide position 12067. The arginine at codon 4023 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		3.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.77		Loss of disorder (P = 0.0107)
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		1.0
Mutation Taster		=6/94	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: rs1556914274; hg19: chrX-53564587; COSMIC: COSV53347743; COSMIC: COSV53347743;