X-53534126-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_031407.7(HUWE1):c.12903A>G(p.Thr4301=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T4301T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (38364 hom., 32390 hem., cov: 22)
  • Exomes 𝑓: 1.0 (366511 hom. 362615 hem.)
  • Failed GnomAD Quality Control
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-53534126-T-C is Benign according to our data. Variant chrX-53534126-T-C is described in ClinVar as [Benign]. Clinvar id is 769214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.12903A>G	p.Thr4301=	synonymous_variant	83/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.12903A>G	p.Thr4301=	synonymous_variant	83/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 109606 AN: 110369 Hom.: 38369 Cov.: 22 AF XY: 0.994 AC XY: 32331 AN XY: 32537 FAILED QC

Gnomad AFR AF: 0.978

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.992

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.999 AC: 1096433 AN: 1097588 Hom.: 366511 Cov.: 42 AF XY: 0.999 AC XY: 362615 AN XY: 362956

Gnomad4 AFR exome AF: 0.974

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.993 AC: 109655 AN: 110420 Hom.: 38364 Cov.: 22 AF XY: 0.994 AC XY: 32390 AN XY: 32598

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 0.997

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.991

Alfa AF: 0.997 Hom.: 9055

Bravo AF: 0.992

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs477171; hg19: chrX-53561087;