rs61742949

chrX-53552694-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031407.7(HUWE1):c.8694G>A(p.Ala2898=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,210,346 control chromosomes in the GnomAD database, including 52 homozygotes. There are 838 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., 419 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (24 hom. 419 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.357

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-53552694-C-T is Benign according to our data. Variant chrX-53552694-C-T is described in ClinVar as [Benign]. Clinvar id is 129247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53552694-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.357 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (1579/112255) while in subpopulation AFR AF= 0.0489 (1511/30904). AF 95% confidence interval is 0.0468. There are 28 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.8694G>A	p.Ala2898=	synonymous_variant	62/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.8694G>A	p.Ala2898=	synonymous_variant	62/84	1	NM_031407.7	P2
HUWE1	ENST00000342160.7	c.8694G>A	p.Ala2898=	synonymous_variant	61/83	5		P2
HUWE1	ENST00000612484.4	c.8667G>A	p.Ala2889=	synonymous_variant	59/81	5		A2
HUWE1	ENST00000704099.1	c.8691G>A	p.Ala2897=	synonymous_variant	61/83

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 1576 AN: 112201 Hom.: 28 Cov.: 23 AF XY: 0.0122 AC XY: 418 AN XY: 34357

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00396

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: 0.000113

Gnomad OTH AF: 0.0133

GnomAD3 exomes AF: 0.00405 AC: 738 AN: 182397 Hom.: 16 AF XY: 0.00263 AC XY: 177 AN XY: 67313

Gnomad AFR exome AF: 0.0505

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00137 AC: 1503 AN: 1098091 Hom.: 24 Cov.: 32 AF XY: 0.00115 AC XY: 419 AN XY: 363467

Gnomad4 AFR exome AF: 0.0477

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.0141 AC: 1579 AN: 112255 Hom.: 28 Cov.: 23 AF XY: 0.0122 AC XY: 419 AN XY: 34421

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.00395

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.00525 Hom.: 28

Bravo AF: 0.0154

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.71
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs61742949; hg19: chrX-53579655;