rs1483703467

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_031407.7(HUWE1):c.5840A>G(p.Tyr1947Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,207,593 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.88

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, X-linked syndromic, Turner type
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HUWE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37159917).

BS2

High AC in GnomAdExome4 at 5 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.5840A>G	p.Tyr1947Cys	missense_variant	Exon 44 of 84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HUWE1	ENST00000262854.11 link	c.5840A>G	p.Tyr1947Cys	missense_variant	Exon 44 of 84	1	NM_031407.7	ENSP00000262854.6	Q7Z6Z7-1
HUWE1	ENST00000342160.7 link	c.5840A>G	p.Tyr1947Cys	missense_variant	Exon 43 of 83	5		ENSP00000340648.3	Q7Z6Z7-1
HUWE1	ENST00000612484.4 link	c.5813A>G	p.Tyr1938Cys	missense_variant	Exon 41 of 81	5		ENSP00000479451.1	Q7Z6Z7-3
HUWE1	ENST00000704099.1 link	c.5840A>G	p.Tyr1947Cys	missense_variant	Exon 43 of 83			ENSP00000515693.1	A0A994J483

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111835

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000166

AC:

AN:

181097

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1095758

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

361156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26365

American (AMR)

AF:

0.000142

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839935

Other (OTH)

AF:

0.00

AC:

AN:

46019

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111835

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33997

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30736

American (AMR)

AF:

0.0000942

AC:

AN:

10613

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53142

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 19, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HUWE1 protein function. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1947 of the HUWE1 protein (p.Tyr1947Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with HUWE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 521256). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.63

.;N;N

PhyloP100

5.9

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.89

.;N;N

REVEL

Benign

0.20

Sift

Benign

0.21

.;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

1.0

.;D;D

Vest4

0.56

MutPred

0.39

.;Loss of phosphorylation at Y1947 (P = 0.0344);Loss of phosphorylation at Y1947 (P = 0.0344);

MVP

0.85

MPC

1.2

ClinPred

0.25

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.84

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over