rs149893977

Positions:

• chrX-53584256-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_031407.7(HUWE1):​c.5091A>G​(p.Gly1697=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,203,279 control chromosomes in the GnomAD database, including 6 homozygotes. There are 930 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 0.0015 (0 hom., 52 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (6 hom. 878 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-53584256-T-C is Benign according to our data. Variant chrX-53584256-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211166.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}. Variant chrX-53584256-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00151 (169/111861) while in subpopulation SAS AF= 0.00532 (14/2631). AF 95% confidence interval is 0.00322. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 52 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.5091A>G	p.Gly1697=	synonymous_variant	41/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.5091A>G	p.Gly1697=	synonymous_variant	41/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 168 AN: 111807 Hom.: 0 Cov.: 22 AF XY: 0.00150 AC XY: 51 AN XY: 33969

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00984

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00493

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00398

GnomAD3 exomes AF: 0.00225 AC: 412 AN: 183375 Hom.: 1 AF XY: 0.00254 AC XY: 172 AN XY: 67827

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.000440

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00228 AC: 2491 AN: 1091418 Hom.: 6 Cov.: 29 AF XY: 0.00246 AC XY: 878 AN XY: 356904

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00519

Gnomad4 FIN exome AF: 0.000593

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00151 AC: 169 AN: 111861 Hom.: 0 Cov.: 22 AF XY: 0.00153 AC XY: 52 AN XY: 34033

Gnomad4 AFR AF: 0.0000976

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00984

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00532

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00205

Gnomad4 OTH AF: 0.00393

Alfa AF: 0.00298 Hom.: 21

Bravo AF: 0.00153

EpiCase AF: 0.00447

EpiControl AF: 0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2016

This alteration is classified as likely 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 disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.71

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: rs149893977; hg19: chrX-53611216;