rs145758265

chrX-53600199-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_031407.7(HUWE1):c.3082A>G(p.Thr1028Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,207,806 control chromosomes in the GnomAD database, including 2 homozygotes. There are 309 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00075 (2 hom. 285 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.44

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HUWE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0046494603).
• BP6: Variant X-53600199-T-C is Benign according to our data. Variant chrX-53600199-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196188.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}. Variant chrX-53600199-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.3082A>G	p.Thr1028Ala	missense_variant	29/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.3082A>G	p.Thr1028Ala	missense_variant	29/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.000740 AC: 83 AN: 112157 Hom.: 0 Cov.: 23 AF XY: 0.000700 AC XY: 24 AN XY: 34301

Gnomad AFR AF: 0.0000324

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: 0.00309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.000960 AC: 176 AN: 183253 Hom.: 0 AF XY: 0.000945 AC XY: 64 AN XY: 67731

Gnomad AFR exome AF: 0.0000760

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: 0.00463

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.000752 AC: 824 AN: 1095596 Hom.: 2 Cov.: 30 AF XY: 0.000789 AC XY: 285 AN XY: 360990

Gnomad4 AFR exome AF: 0.0000379

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: 0.00540

Gnomad4 NFE exome AF: 0.000672

Gnomad4 OTH exome AF: 0.000826

GnomAD4 genome AF: 0.000740 AC: 83 AN: 112210 Hom.: 0 Cov.: 23 AF XY: 0.000698 AC XY: 24 AN XY: 34364

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00309

Gnomad4 NFE AF: 0.00117

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.00108 Hom.: 44

Bravo AF: 0.000400

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	This variant is associated with the following publications: (PMID: 24307393) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2015

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 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. -

HUWE1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	19
Dann	Benign	0.84
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.075
MVP		0.44
MPC		0.92
ClinPred		0.0091	T
GERP RS		4.1
Varity_R		0.050
gMVP		0.19

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

Other links and lift over

dbSNP: rs145758265; hg19: chrX-53627159;