chrX-53627451-T-C

Position:

chrX-53627451-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 13/19 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.

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 id is 129252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53627451-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.1448A>G	p.Asn483Ser	missense_variant	17/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11 linkuse as main transcript	c.1448A>G	p.Asn483Ser	missense_variant	17/84	1	NM_031407.7	ENSP00000262854	P2	Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2068

AN:

110497

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

566

AN XY:

32719

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

GnomAD3 exomes

AF:

0.0177

AC:

3236

AN:

182765

Hom.:

AF XY:

0.0171

AC XY:

1151

AN XY:

67239

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 SAS exome

AF:

0.000637

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

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0746

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000781

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.0271

Gnomad4 OTH exome

AF:

0.0244

GnomAD4 genome

AF:

0.0187

AC:

2067

AN:

110542

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

565

AN XY:

32774

show subpopulations

Gnomad4 AFR

AF:

0.00305

Gnomad4 AMR

AF:

0.0231

Gnomad4 ASJ

AF:

0.0779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000380

Gnomad4 FIN

AF:

0.0129

Gnomad4 NFE

AF:

0.0266

Gnomad4 OTH

AF:

0.0302

Alfa

AF:

0.0259

Hom.:

1077

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 08, 2013

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2016

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

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

MutationTaster

Benign

1.0

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over