Variant X-53539792-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The ENST00000262854.11(HUWE1):c.11497G>C(p.Gly3833Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,208,828 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

HUWE1
ENST00000262854.11 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.16

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 -13 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=0.15632474).

BP6

Variant X-53539792-C-G is Benign according to our data. Variant chrX-53539792-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.11497G>C	p.Gly3833Arg	missense_variant	75/84	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.11497G>C	p.Gly3833Arg	missense_variant	75/84	1	NM_031407.7	ENSP00000262854	P2	Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112319

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34465

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000449

AC:

AN:

178263

Hom.:

AF XY:

0.0000317

AC XY:

AN XY:

63147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000379

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1096509

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361961

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000372

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112319

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34465

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.33

.;T;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L;L

MutationTaster

Benign

0.89

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

.;N;N

REVEL

Benign

0.072

Sift

Benign

0.19

.;T;T

Sift4G

Uncertain

0.036

D;D;D

Polyphen

0.23

.;B;B

Vest4

0.27

MutPred

0.15

.;Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);

MVP

0.51

MPC

1.6

ClinPred

0.11

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.28

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