chrX-53629522-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_031407.7(HUWE1):c.957G>T(p.Gln319His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,155,237 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 48 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.00017 ( 0 hom. 47 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.13

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117096186).

BP6

Variant X-53629522-C-A is Benign according to our data. Variant chrX-53629522-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211172.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000171 (179/1044434) while in subpopulation NFE AF = 0.000223 (177/793262). AF 95% confidence interval is 0.000196. There are 0 homozygotes in GnomAdExome4. There are 47 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 179 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.957G>T	p.Gln319His	missense_variant	Exon 13 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 link	c.957G>T	p.Gln319His	missense_variant	Exon 13 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110803

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

183292

AF XY:

0.000133

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

179

AN:

1044434

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

321328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25404

American (AMR)

AF:

0.00

AC:

AN:

35144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19045

East Asian (EAS)

AF:

0.00

AC:

AN:

29942

South Asian (SAS)

AF:

0.00

AC:

AN:

52923

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40451

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3996

European-Non Finnish (NFE)

AF:

0.000223

AC:

177

AN:

793262

Other (OTH)

AF:

0.0000452

AC:

AN:

44267

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000271

AC:

AN:

110803

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

33027

show subpopulations

African (AFR)

AF:

0.0000329

AC:

AN:

30419

American (AMR)

AF:

0.00

AC:

AN:

10418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5855

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52934

Other (OTH)

AF:

0.00

AC:

AN:

1489

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

Genome Hom

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:

0.0000434

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 24, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

not provided

Benign:1

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.21

.;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.26

N;N;N

PhyloP100

1.1

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.88

.;N;N

REVEL

Benign

0.028

Sift

Benign

0.96

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.090

.;B;B

Vest4

0.41

MutPred

0.42

Loss of ubiquitination at K324 (P = 0.1216);Loss of ubiquitination at K324 (P = 0.1216);Loss of ubiquitination at K324 (P = 0.1216);

MVP

0.72

MPC

1.1

ClinPred

0.073

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.52

Mutation Taster

=98/2

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