rs142126065

Positions:

chrX-53593442-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The ENST00000262854.11(HUWE1):c.3663G>A(p.Ser1221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,209,598 control chromosomes in the GnomAD database, including 3 homozygotes. There are 424 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., 36 hem., cov: 24)

Exomes 𝑓: 0.0010 ( 3 hom. 388 hem. )

Consequence

HUWE1
ENST00000262854.11 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -2.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant X-53593442-C-T is Benign according to our data. Variant chrX-53593442-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196796.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chrX-53593442-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000973 (109/112028) while in subpopulation AMR AF= 0.00291 (31/10636). AF 95% confidence interval is 0.00211. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.3663G>A	p.Ser1221=	synonymous_variant	32/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 linkuse as main transcript	c.3663G>A	p.Ser1221=	synonymous_variant	32/84	1	NM_031407.7	ENSP00000262854	P2	Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

109

AN:

111974

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

34150

show subpopulations

Gnomad AFR

AF:

0.000423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00292

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.000644

AC:

118

AN:

183335

Hom.:

AF XY:

0.000885

AC XY:

AN XY:

67785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000693

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000420

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.00104

AC:

1136

AN:

1097570

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

388

AN XY:

362934

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000767

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000665

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.000973

AC:

109

AN:

112028

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

34214

show subpopulations

Gnomad4 AFR

AF:

0.000422

Gnomad4 AMR

AF:

0.00291

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00111

Gnomad4 OTH

AF:

0.00330

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000997

EpiCase

AF:

0.00136

EpiControl

AF:

0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

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	Dec 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 30, 2017

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

1.7

DANN

Benign

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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