rs41307640

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031407.7(HUWE1):c.1448A>G(p.Asn483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,197,201 control chromosomes in the GnomAD database, including 320 homozygotes. There are 8,633 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 Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 26 hom., 565 hem., cov: 22)

Exomes 𝑓: 0.024 ( 294 hom. 8068 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.03

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015617311).

BP6

Variant X-53627451-T-C is Benign according to our data. Variant chrX-53627451-T-C is described in ClinVar as Benign. ClinVar VariationId is 129252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2067/110542) while in subpopulation NFE AF = 0.0266 (1405/52872). AF 95% confidence interval is 0.0254. There are 26 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 2067 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.1448A>G	p.Asn483Ser	missense_variant	Exon 17 of 84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 link	c.1448A>G	p.Asn483Ser	missense_variant	Exon 17 of 84	1	NM_031407.7	ENSP00000262854.6		Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2068

AN:

110497

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00306

Gnomad AMI

AF:

0.00437

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000757

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0305

GnomAD2 exomes

AF:

0.0177

AC:

3236

AN:

182765

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0765

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0143

Gnomad NFE exome

AF:

0.0242

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.0241

AC:

26137

AN:

1086659

Hom.:

294

Cov.:

AF XY:

0.0228

AC XY:

8068

AN XY:

353459

show subpopulations

African (AFR)

AF:

0.00320

AC:

AN:

26230

American (AMR)

AF:

0.0107

AC:

377

AN:

35139

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

1438

AN:

19281

East Asian (EAS)

AF:

0.00

AC:

AN:

30085

South Asian (SAS)

AF:

0.000781

AC:

AN:

53750

European-Finnish (FIN)

AF:

0.0125

AC:

505

AN:

40415

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.0271

AC:

22519

AN:

831985

Other (OTH)

AF:

0.0244

AC:

1114

AN:

45672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

760

1519

2279

3038

3798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.0187

AC:

2067

AN:

110542

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

565

AN XY:

32774

show subpopulations

African (AFR)

AF:

0.00305

AC:

AN:

30494

American (AMR)

AF:

0.0231

AC:

239

AN:

10327

Ashkenazi Jewish (ASJ)

AF:

0.0779

AC:

205

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.000380

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.0129

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0266

AC:

1405

AN:

52872

Other (OTH)

AF:

0.0302

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0247

Hom.:

1097

Bravo

AF:

0.0189

ESP6500AA

AF:

0.00391

AC:

ESP6500EA

AF:

0.0275

AC:

185

ExAC

AF:

0.0167

AC:

2023

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.2

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.11

.;T;T

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.81

T;.;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.52

N;N;N

PhyloP100

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

0.71

.;N;N

REVEL

Benign

0.024

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

.;B;B

Vest4

0.037

MPC

0.75

ClinPred

0.0028

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.23

Mutation Taster

=97/3

polymorphism (auto)

(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