rs782428636

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.6149G>A(p.Arg2050Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,209,429 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).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

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:2B:1

Conservation

PhyloP100: 2.03

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
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=0.11966106).

BP6

Variant X-53573913-C-T is Benign according to our data. Variant chrX-53573913-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521794.

BS2

High AC in GnomAdExome4 at 7 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031407.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HUWE1	NM_031407.7	MANE Select	c.6149G>A	p.Arg2050Gln	missense	Exon 47 of 84	NP_113584.3
HUWE1	NM_001441057.1		c.6149G>A	p.Arg2050Gln	missense	Exon 46 of 83	NP_001427986.1
HUWE1	NM_001441051.1		c.6146G>A	p.Arg2049Gln	missense	Exon 47 of 84	NP_001427980.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HUWE1	ENST00000262854.11	TSL:1 MANE Select	c.6149G>A	p.Arg2050Gln	missense	Exon 47 of 84	ENSP00000262854.6	Q7Z6Z7-1
HUWE1	ENST00000342160.7	TSL:5	c.6149G>A	p.Arg2050Gln	missense	Exon 46 of 83	ENSP00000340648.3	Q7Z6Z7-1
HUWE1	ENST00000612484.4	TSL:5	c.6122G>A	p.Arg2041Gln	missense	Exon 44 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000652

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183478

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097821

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363193

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26398

American (AMR)

AF:

0.0000284

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54129

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841866

Other (OTH)

AF:

0.0000217

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000179

AC:

AN:

111608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33796

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30656

American (AMR)

AF:

0.00

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2649

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53095

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0068

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

2.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.36

REVEL

Benign

0.10

Sift

Benign

0.099

Sift4G

Benign

0.45

Polyphen

0.20

Vest4

0.13

MutPred

0.23

Loss of MoRF binding (P = 0.0239)

MVP

0.64

MPC

1.1

ClinPred

0.21

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over