NM_031407.7:c.1115A>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

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 (★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000038 ( 0 hom. 4 hem. )

Consequence

HUWE1
NM_031407.7 missense, splice_region

Scores

5
9
3
Splicing: ADA: 0.1977
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant in the HUWE1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 8.8732 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
BS2
High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUWE1NM_031407.7 linkc.1115A>T p.Asp372Val missense_variant, splice_region_variant Exon 15 of 84 ENST00000262854.11 NP_113584.3 Q7Z6Z7-1A0A024R9W5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HUWE1ENST00000262854.11 linkc.1115A>T p.Asp372Val missense_variant, splice_region_variant Exon 15 of 84 1 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1

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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000485
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045617; hg19: chrX-53655571; API