chrX-53554829-T-C

Variant names:

• chrX-53554829-T-C
• rs202214456
• NM_031407.7:c.8298A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031407.7(HUWE1):​c.8298A>G​(p.Gln2766Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,208,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 290 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00082 (0 hom. 279 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.744

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-53554829-T-C is Benign according to our data. Variant chrX-53554829-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 435477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.744 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000503 (56/111276) while in subpopulation NFE AF= 0.000774 (41/53005). AF 95% confidence interval is 0.000585. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.8298A>G	p.Gln2766Gln	synonymous_variant	Exon 61 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.8298A>G	p.Gln2766Gln	synonymous_variant	Exon 61 of 84	1	NM_031407.7	ENSP00000262854.6
HUWE1	ENST00000342160.7	c.8298A>G	p.Gln2766Gln	synonymous_variant	Exon 60 of 83	5		ENSP00000340648.3
HUWE1	ENST00000612484.4	c.8271A>G	p.Gln2757Gln	synonymous_variant	Exon 58 of 81	5		ENSP00000479451.1
HUWE1	ENST00000704099.1	c.8295A>G	p.Gln2765Gln	synonymous_variant	Exon 60 of 83			ENSP00000515693.1

Frequencies

GnomAD3 genomes AF: 0.000503 AC: 56 AN: 111222 Hom.: 0 Cov.: 22 AF XY: 0.000329 AC XY: 11 AN XY: 33428

Gnomad AFR AF: 0.000426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

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: 0.000773

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000328 AC: 60 AN: 182922 Hom.: 0 AF XY: 0.000237 AC XY: 16 AN XY: 67392

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000576

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000819 AC: 899 AN: 1097247 Hom.: 0 Cov.: 30 AF XY: 0.000769 AC XY: 279 AN XY: 362607

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.000717

GnomAD4 genome AF: 0.000503 AC: 56 AN: 111276 Hom.: 0 Cov.: 22 AF XY: 0.000328 AC XY: 11 AN XY: 33492

Gnomad4 AFR AF: 0.000425

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000774

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000738 Hom.: 4

Bravo AF: 0.000559

EpiCase AF: 0.000437

EpiControl AF: 0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HUWE1: BP4, BP7 -

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.25
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs202214456; hg19: chrX-53581790;