rs145758265

Positions:

chrX-53600199-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_031407.7(HUWE1):c.3082A>G(p.Thr1028Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,207,806 control chromosomes in the GnomAD database, including 2 homozygotes. There are 309 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., 24 hem., cov: 23)

Exomes 𝑓: 0.00075 ( 2 hom. 285 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.44

Variant links:

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 links:

HUWE1 (HGNC:):

HUWE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046494603).

BP6

Variant X-53600199-T-C is Benign according to our data. Variant chrX-53600199-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196188.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chrX-53600199-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.3082A>G	p.Thr1028Ala	missense_variant	29/84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 linkuse as main transcript	c.3082A>G	p.Thr1028Ala	missense_variant	29/84	1	NM_031407.7	ENSP00000262854.6		Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.000740

AC:

AN:

112157

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

AN XY:

34301

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00309

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00117

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.000960

AC:

176

AN:

183253

Hom.:

AF XY:

0.000945

AC XY:

AN XY:

67731

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000884

GnomAD4 exome

AF:

0.000752

AC:

824

AN:

1095596

Hom.:

Cov.:

AF XY:

0.000789

AC XY:

285

AN XY:

360990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00540

Gnomad4 NFE exome

AF:

0.000672

Gnomad4 OTH exome

AF:

0.000826

GnomAD4 genome

AF:

0.000740

AC:

AN:

112210

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

34364

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00309

Gnomad4 NFE

AF:

0.00117

Gnomad4 OTH

AF:

0.000654

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.00134

AC:

163

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	This variant is associated with the following publications: (PMID: 24307393) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2015

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HUWE1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.26

.;T;T

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.47

.;N;N

REVEL

Benign

0.052

Sift

Benign

0.73

.;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.075

MVP

0.44

MPC

0.92

ClinPred

0.0091

GERP RS

4.1

Varity_R

0.050

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over