rs148129382

Variant names:

• chrX-53631606-A-G
• rs148129382
• NM_031407.7:c.654T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_031407.7(HUWE1):​c.654T>C​(p.Ser218Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,186,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 306 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., 14 hem., cov: 22)
  • Exomes 𝑓: 0.00083 (0 hom. 292 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.33

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-53631606-A-G is Benign according to our data. Variant chrX-53631606-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211169.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000536 (60/111952) while in subpopulation NFE AF= 0.000885 (47/53096). AF 95% confidence interval is 0.000683. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.654T>C	p.Ser218Ser	synonymous_variant	Exon 10 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.654T>C	p.Ser218Ser	synonymous_variant	Exon 10 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 60 AN: 111899 Hom.: 0 Cov.: 22 AF XY: 0.000411 AC XY: 14 AN XY: 34067

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000474

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.000491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000885

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000552 AC: 101 AN: 182973 Hom.: 0 AF XY: 0.000578 AC XY: 39 AN XY: 67517

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.000991

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000831 AC: 893 AN: 1074743 Hom.: 0 Cov.: 27 AF XY: 0.000850 AC XY: 292 AN XY: 343587

Gnomad4 AFR exome AF: 0.0000770

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000149

Gnomad4 FIN exome AF: 0.000913

Gnomad4 NFE exome AF: 0.000982

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.000536 AC: 60 AN: 111952 Hom.: 0 Cov.: 22 AF XY: 0.000410 AC XY: 14 AN XY: 34130

Gnomad4 AFR AF: 0.0000648

Gnomad4 AMR AF: 0.000473

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000373

Gnomad4 FIN AF: 0.000491

Gnomad4 NFE AF: 0.000885

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000763 Hom.: 6

Bravo AF: 0.000423

EpiCase AF: 0.000491

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Sep 04, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 27, 2017

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	-0.42
CADD	Benign	10
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148129382; hg19: chrX-53658558;