rs797045617

Variant names:

• chrX-53628620-T-A
• rs797045617
• NM_031407.7:c.1115A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53628620-T-A
• chrX-53628620-T-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_031407.7(HUWE1):​c.1115A>T​(p.Asp372Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,064,501 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D372Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 4 hem.)
• Consequence: HUWE1 NM_031407.7 missense, splice_region
• Scores: Splicing: ADA: 0.1977
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.1115A>T	p.Asp372Val	missense_variant, splice_region_variant	Exon 15 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.1115A>T	p.Asp372Val	missense_variant, splice_region_variant	Exon 15 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000376 AC: 4 AN: 1064501 Hom.: 0 Cov.: 32 AF XY: 0.0000115 AC XY: 4 AN XY: 347259

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 25166

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 29821

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 18895

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 27686

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 50655

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 38732

Gnomad4 NFE exome AF: 0.00000485 AC: 4 AN: 824572

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 44868

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	.;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		0.97	.;D;D
Vest4		0.74
MutPred		0.42		Gain of catalytic residue at D372 (P = 0.0223);Gain of catalytic residue at D372 (P = 0.0223);Gain of catalytic residue at D372 (P = 0.0223);
MVP		0.92
MPC		1.9
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.43
gMVP		0.84
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.49
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: rs797045617; hg19: chrX-53655571;