rs781928056

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_031407.7(HUWE1):c.1000A>G(p.Ile334Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,094,540 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I334T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.76

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25045785).

BP6

Variant X-53628866-T-C is Benign according to our data. Variant chrX-53628866-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211157.

BS2

High AC in GnomAdExome4 at 7 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.1000A>G	p.Ile334Val	missense_variant	Exon 14 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.1000A>G	p.Ile334Val	missense_variant	Exon 14 of 84	1	NM_031407.7	ENSP00000262854.6		Q7Z6Z7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182541

AF XY:

0.0000149

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:

0.000221

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1094540

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

359962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26323

American (AMR)

AF:

0.0000853

AC:

AN:

35182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19353

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

53992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

838853

Other (OTH)

AF:

0.0000217

AC:

AN:

45994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 14, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The I334V variant in the HUWE1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I334V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, the I334V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I334V as a variant of uncertain significance. -

not specified

Benign:1

Dec 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely 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

-0.30

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

.;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;.;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

L;L;L

PhyloP100

7.8

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.53

.;N;N

REVEL

Benign

0.21

Sift

Benign

0.25

.;T;T

Sift4G

Benign

0.39

T;T;T

Polyphen

0.66

.;P;P

Vest4

0.45

MutPred

0.70

Loss of catalytic residue at I334 (P = 0.0612);Loss of catalytic residue at I334 (P = 0.0612);Loss of catalytic residue at I334 (P = 0.0612);

MVP

0.79

MPC

1.2

ClinPred

0.39

GERP RS

4.5

PromoterAI

0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.47

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over