rs144449744

chrX-53588493-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_031407.7(HUWE1):c.4503C>T(p.Pro1501=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,204,481 control chromosomes in the GnomAD database, including 1 homozygotes. There are 467 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., 28 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (1 hom. 439 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.261

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-53588493-G-A is Benign according to our data. Variant chrX-53588493-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53588493-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.261 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.4503C>T	p.Pro1501=	synonymous_variant	37/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.4503C>T	p.Pro1501=	synonymous_variant	37/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 100 AN: 111120 Hom.: 0 Cov.: 23 AF XY: 0.000840 AC XY: 28 AN XY: 33316

Gnomad AFR AF: 0.000164

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: 0.000509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.000672

GnomAD3 exomes AF: 0.000843 AC: 145 AN: 171996 Hom.: 0 AF XY: 0.000921 AC XY: 53 AN XY: 57562

Gnomad AFR exome AF: 0.000239

Gnomad AMR exome AF: 0.0000751

Gnomad ASJ exome AF: 0.000956

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000464

GnomAD4 exome AF: 0.00132 AC: 1438 AN: 1093311 Hom.: 1 Cov.: 30 AF XY: 0.00122 AC XY: 439 AN XY: 359229

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.0000574

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000299

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.000632

GnomAD4 genome AF: 0.000900 AC: 100 AN: 111170 Hom.: 0 Cov.: 23 AF XY: 0.000839 AC XY: 28 AN XY: 33376

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000509

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.00148 Hom.: 11

Bravo AF: 0.000865

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 21, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2021

This variant is classified as likely 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	-0.72
Cadd	Benign	4.5
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs144449744; hg19: chrX-53615453;