X-53534049-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_031407.7(HUWE1):c.12980G>A(p.Arg4327Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,209,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 0.0000018 ( 0 hom. 0 hem. )

Consequence

HUWE1
NM_031407.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.00

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the HUWE1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 8.8732 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.

PP5

Variant X-53534049-C-T is Pathogenic according to our data. Variant chrX-53534049-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1077131.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.12980G>A	p.Arg4327Gln	missense_variant	Exon 83 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.12980G>A	p.Arg4327Gln	missense_variant	Exon 83 of 84	1	NM_031407.7	ENSP00000262854.6		Q7Z6Z7-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111755

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33931

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000109

AC:

AN:

183506

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67936

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097942

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111755

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33931

show subpopulations

Gnomad4 AFR

AF:

0.0000325

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:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Abnormal corpus callosum morphology

Pathogenic:1

May 12, 2021

Genetics Institute, Tel Aviv Sourasky Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jun 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35229910) -

Intellectual disability, X-linked syndromic, Turner type

Uncertain:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.12980G>A(p.Arg4327Gln) variant in HUWE1 gene has been reported previously in X-linked state in individual(s) affected with central nervous system (CNS) anomalies (Yaron et al., 2022). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance. However, study of the variant in multiple affected individuals and its functional impact on the protein is required to determine the pathogenicity of the variant. The amino acid Arg at position 4327 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg4327Gln in HUWE1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.2

.;M;M

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.6

.;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

.;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.33

MutPred

0.53

.;Loss of ubiquitination at K4322 (P = 0.0949);Loss of ubiquitination at K4322 (P = 0.0949);

MVP

0.90

MPC

1.6

ClinPred

0.68

GERP RS

5.4

Varity_R

0.91

gMVP

0.92

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