rs147480463

Positions:

• chrX-53575148-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 3/3 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:3
• Conservation: PhyloP100: -0.545

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 -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. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.6097+7A>C		splice_region_variant, intron_variant		1	NM_031407.7	P2
HUWE1	ENST00000342160.7	c.6097+7A>C		splice_region_variant, intron_variant		5		P2
HUWE1	ENST00000612484.4	c.6070+7A>C		splice_region_variant, intron_variant		5		A2
HUWE1	ENST00000704099.1	c.6094+7A>C		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 715 AN: 111915 Hom.: 4 Cov.: 23 AF XY: 0.00554 AC XY: 189 AN XY: 34111

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.: 1 AF XY: 0.00128 AC XY: 74 AN XY: 57799

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.: 5 Cov.: 27 AF XY: 0.000488 AC XY: 168 AN XY: 343986

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.: 4 Cov.: 23 AF XY: 0.00553 AC XY: 189 AN XY: 34176

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.: 13

Bravo AF: 0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2014

- -

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

Other links and lift over

dbSNP: rs147480463; hg19: chrX-53602108;