rs41306894

Positions:

• chrX-53548208-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_031407.7(HUWE1):​c.10101G>A​(p.Arg3367Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,208,499 control chromosomes in the GnomAD database, including 56 homozygotes. There are 3,820 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (5 hom., 248 hem., cov: 23)
  • Exomes 𝑓: 0.010 (51 hom. 3572 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.01

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-53548208-C-T is Benign according to our data. Variant chrX-53548208-C-T is described in ClinVar as [Benign]. Clinvar id is 129248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00717 (806/112452) while in subpopulation NFE AF= 0.0107 (572/53285). AF 95% confidence interval is 0.01. There are 5 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.10101G>A	p.Arg3367Arg	synonymous_variant	68/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.10101G>A	p.Arg3367Arg	synonymous_variant	68/84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 806 AN: 112398 Hom.: 5 Cov.: 23 AF XY: 0.00718 AC XY: 248 AN XY: 34560

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00367

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00397

GnomAD3 exomes AF: 0.00773 AC: 1357 AN: 175555 Hom.: 1 AF XY: 0.00732 AC XY: 452 AN XY: 61767

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00367

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00791

GnomAD4 exome AF: 0.0102 AC: 11147 AN: 1096047 Hom.: 51 Cov.: 31 AF XY: 0.00988 AC XY: 3572 AN XY: 361581

Gnomad4 AFR exome AF: 0.000834

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.00186

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00897

GnomAD4 genome AF: 0.00717 AC: 806 AN: 112452 Hom.: 5 Cov.: 23 AF XY: 0.00716 AC XY: 248 AN XY: 34624

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00328

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00368

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00392

Alfa AF: 0.00892 Hom.: 67

Bravo AF: 0.00555

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 15, 2015

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 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	-0.46
CADD	Benign	9.4
DANN	Benign	0.68

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: rs41306894; hg19: chrX-53575169;