NM_031407.7:c.1953C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031407.7(HUWE1):​c.1953C>G​(p.Pro651Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,203,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 64 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 0.00099 ( 0 hom., 35 hem., cov: 23)
Exomes 𝑓: 0.00010 ( 0 hom. 29 hem. )

Consequence

HUWE1
NM_031407.7 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.188

Publications

0 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant X-53616974-G-C is Benign according to our data. Variant chrX-53616974-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 435482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.188 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000986 (110/111511) while in subpopulation AFR AF = 0.00355 (109/30700). AF 95% confidence interval is 0.00301. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
BS2
High AC in GnomAd4 at 110 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUWE1NM_031407.7 linkc.1953C>G p.Pro651Pro synonymous_variant Exon 21 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.1953C>G p.Pro651Pro synonymous_variant Exon 21 of 84 1 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1

Frequencies

GnomAD3 genomes
AF:
0.000987
AC:
110
AN:
111459
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00356
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.000664
GnomAD2 exomes
AF:
0.000259
AC:
47
AN:
181123
AF XY:
0.000167
show subpopulations
Gnomad AFR exome
AF:
0.00354
Gnomad AMR exome
AF:
0.0000367
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
112
AN:
1092169
Hom.:
0
Cov.:
30
AF XY:
0.0000811
AC XY:
29
AN XY:
357799
show subpopulations
African (AFR)
AF:
0.00380
AC:
100
AN:
26286
American (AMR)
AF:
0.0000285
AC:
1
AN:
35121
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19321
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30167
South Asian (SAS)
AF:
0.0000186
AC:
1
AN:
53760
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40507
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4115
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
836999
Other (OTH)
AF:
0.000218
AC:
10
AN:
45893
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
5
10
14
19
24
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000986
AC:
110
AN:
111511
Hom.:
0
Cov.:
23
AF XY:
0.00104
AC XY:
35
AN XY:
33727
show subpopulations
African (AFR)
AF:
0.00355
AC:
109
AN:
30700
American (AMR)
AF:
0.00
AC:
0
AN:
10526
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2646
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3550
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2630
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5982
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
215
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53051
Other (OTH)
AF:
0.000656
AC:
1
AN:
1525
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.518
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000569
Hom.:
3
Bravo
AF:
0.00110

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 11, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Oct 31, 2016
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Jan 17, 2017
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HUWE1-related disorder Benign:1
Aug 12, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
6.3
DANN
Benign
0.75
PhyloP100
-0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs139152809; hg19: chrX-53643935; API