rs147480463

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031407.7(HUWE1):c.6097+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,188,360 control chromosomes in the GnomAD database, including 9 homozygotes. There are 357 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., 189 hem., cov: 23)

Exomes 𝑓: 0.00065 ( 5 hom. 168 hem. )

Consequence

HUWE1
NM_031407.7 splice_region, intron

Scores

Splicing: ADA: 0.0001033

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.545

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-53575148-T-G is Benign according to our data. Variant chrX-53575148-T-G is described in ClinVar as [Benign]. Clinvar id is 211167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00639 (715/111970) while in subpopulation AFR AF= 0.0221 (681/30805). AF 95% confidence interval is 0.0207. There are 4 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7 linkuse as main transcript	c.6097+7A>C		splice_region_variant, intron_variant		ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11 linkuse as main transcript	c.6097+7A>C	splice_region_variant, intron_variant	1	NM_031407.7	P2	Q7Z6Z7-1
HUWE1	ENST00000342160.7 linkuse as main transcript	c.6097+7A>C	splice_region_variant, intron_variant	5		P2	Q7Z6Z7-1
HUWE1	ENST00000612484.4 linkuse as main transcript	c.6070+7A>C	splice_region_variant, intron_variant	5		A2	Q7Z6Z7-3
HUWE1	ENST00000704099.1 linkuse as main transcript	c.6094+7A>C	splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00639

AC:

715

AN:

111915

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

189

AN XY:

34111

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00226

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:

0.0000188

Gnomad OTH

AF:

0.00597

GnomAD3 exomes

AF:

0.00175

AC:

301

AN:

172085

Hom.:

AF XY:

0.00128

AC XY:

AN XY:

57799

show subpopulations

Gnomad AFR exome

AF:

0.0221

Gnomad AMR exome

AF:

0.000865

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.000697

GnomAD4 exome

AF:

0.000650

AC:

700

AN:

1076390

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

168

AN XY:

343986

show subpopulations

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000850

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.00639

AC:

715

AN:

111970

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

189

AN XY:

34176

show subpopulations

Gnomad4 AFR

AF:

0.0221

Gnomad4 AMR

AF:

0.00226

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00590

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2014

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

Cadd

Benign

4.3

Dann

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.040

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