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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_031407.7(HUWE1):c.11497G>A(p.Gly3833Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,828 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Not reported in ClinVar

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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). The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. GenCC has associacion of the 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=0.18279162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.11497G>A	p.Gly3833Arg	missense_variant	75/84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 link	c.11497G>A	p.Gly3833Arg	missense_variant	75/84	1	NM_031407.7	ENSP00000262854.6		Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112319

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34465

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000112

AC:

AN:

178263

Hom.:

AF XY:

0.0000158

AC XY:

AN XY:

63147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000253

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096509

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361961

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112319

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34465

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.33

.;T;T

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L;L

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

0.40

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over