rs61742949

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031407.7(HUWE1):c.8694G>A(p.Ala2898Ala) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.357

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 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. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7 link	c.8694G>A	p.Ala2898Ala	synonymous_variant	Exon 62 of 84	ENST00000262854.11	NP_113584.3	Q7Z6Z7-1A0A024R9W5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HUWE1	ENST00000262854.11 link	c.8694G>A	p.Ala2898Ala	synonymous_variant	Exon 62 of 84	1	NM_031407.7	ENSP00000262854.6	Q7Z6Z7-1
HUWE1	ENST00000342160.7 link	c.8694G>A	p.Ala2898Ala	synonymous_variant	Exon 61 of 83	5		ENSP00000340648.3	Q7Z6Z7-1
HUWE1	ENST00000612484.4 link	c.8667G>A	p.Ala2889Ala	synonymous_variant	Exon 59 of 81	5		ENSP00000479451.1	Q7Z6Z7-3
HUWE1	ENST00000704099.1 link	c.8691G>A	p.Ala2897Ala	synonymous_variant	Exon 61 of 83			ENSP00000515693.1	A0A994J483

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

1576

AN:

112201

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

418

AN XY:

34357

show subpopulations

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.:

AF XY:

0.00263

AC XY:

177

AN XY:

67313

show subpopulations

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.:

Cov.:

AF XY:

0.00115

AC XY:

419

AN XY:

363467

show subpopulations

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.:

Cov.:

AF XY:

0.0122

AC XY:

419

AN XY:

34421

show subpopulations

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.:

Bravo

AF:

0.0154

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 10, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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