rs1557036757

chrX-53647375-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_031407.7(HUWE1):c.344C>T(p.Ser115Phe) variant causes a missense change involving the alteration of a 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: 23)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.35

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HUWE1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-53647375-G-A is Pathogenic according to our data. Variant chrX-53647375-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.344C>T	p.Ser115Phe	missense_variant	6/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.344C>T	p.Ser115Phe	missense_variant	6/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a de novo change in a female patient with X-linked intellectual disability (PMID: 29180823). That reported patient had abnormal X-inactivation studies (PMID: 29180823). It is absent from the gnomAD population database and thus is presumed to be rare. The c.344C>T (p.Ser115Phe) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.344C>T (p.Ser115Phe) variant is classified as Likely Pathogenic. -

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	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.047	D
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95
MutPred		0.87		Loss of disorder (P = 0.0098);Loss of disorder (P = 0.0098);Loss of disorder (P = 0.0098);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557036757; hg19: chrX-53674318; COSMIC: COSV53341725; COSMIC: COSV53341725;