X-53593585-G-C

Position:

chrX-53593585-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_031407.7(HUWE1):c.3520C>G(p.Leu1174Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,200,438 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000012 ( 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: 4.03

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 Likely_benign. Variant got -5 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=0.29449558).

BP6

Variant X-53593585-G-C is Benign according to our data. Variant chrX-53593585-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521324.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.3520C>G	p.Leu1174Val	missense_variant	32/84	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.3520C>G	p.Leu1174Val	missense_variant	32/84	1	NM_031407.7	ENSP00000262854	P2	Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34280

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

182105

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66885

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1088336

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

353944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000381

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2021

The c.3520C>G (p.L1174V) alteration is located in exon 32 (coding exon 29) of the HUWE1 gene. This alteration results from a C to G substitution at nucleotide position 3520, causing the leucine (L) at amino acid position 1174 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the HUWE1 c.3520C>G alteration was observed in 0.003% (5/182,105) of total alleles studied, with a frequency of 0.007% (2/27,384) in the Latino subpopulation. This amino acid position is highly conserved in available vertebrate species. The p.L1174V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

.;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

.;N;N

REVEL

Benign

0.22

Sift

Benign

0.093

.;T;T

Sift4G

Benign

0.093

T;T;T

Polyphen

0.61

.;P;P

Vest4

0.45

MutPred

0.38

.;Loss of stability (P = 0.0789);Loss of stability (P = 0.0789);

MVP

0.81

MPC

1.5

ClinPred

0.24

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.22

gMVP

0.49

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