X-53608926-G-T

Variant names:

• chrX-53608926-G-T
• rs143891272
• NM_031407.7:c.2262-17C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031407.7(HUWE1):​c.2262-17C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,038,449 control chromosomes in the GnomAD database, including 48 homozygotes. There are 706 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., 406 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (21 hom. 300 hem.)
• Consequence: HUWE1 NM_031407.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.329
• Publications: 0 publications found

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]

HUWE1 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked syndromic, Turner type

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-53608926-G-T is Benign according to our data. Variant chrX-53608926-G-T is described in ClinVar as Benign. ClinVar VariationId is 445807.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 = 0.0138 (1551/112251) while in subpopulation AFR AF = 0.0479 (1479/30870). AF 95% confidence interval is 0.0459. There are 27 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1551 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.2262-17C>A		intron_variant	Intron 23 of 83	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.2262-17C>A		intron_variant	Intron 23 of 83	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1548 AN: 112199 Hom.: 27 Cov.: 23

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00434

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: 0.000113

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.00396 AC: 724 AN: 183003 AF XY: 0.00254

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00135 AC: 1249 AN: 926198 Hom.: 21 Cov.: 19 AF XY: 0.00118 AC XY: 300 AN XY: 254026

African (AFR) AF: 0.0448 AC: 1033 AN: 23063

American (AMR) AF: 0.00243 AC: 85 AN: 35014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18307

East Asian (EAS) AF: 0.00 AC: 0 AN: 29478

South Asian (SAS) AF: 0.000158 AC: 8 AN: 50542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40453

Middle Eastern (MID) AF: 0.00159 AC: 6 AN: 3768

European-Non Finnish (NFE) AF: 0.0000263 AC: 18 AN: 685118

Other (OTH) AF: 0.00245 AC: 99 AN: 40455

GnomAD4 genome AF: 0.0138 AC: 1551 AN: 112251 Hom.: 27 Cov.: 23 AF XY: 0.0118 AC XY: 406 AN XY: 34437

African (AFR) AF: 0.0479 AC: 1479 AN: 30870

American (AMR) AF: 0.00433 AC: 46 AN: 10618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53232

Other (OTH) AF: 0.0130 AC: 20 AN: 1534

Alfa AF: 0.00199 Hom.: 12

Bravo AF: 0.0152

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: 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	-0.81
CADD	Benign	8.3
DANN	Benign	0.60
PhyloP100		0.33
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs143891272; hg19: chrX-53635887;