NM_031407.7:c.10035+6G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_031407.7(HUWE1):​c.10035+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,186,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 6 hem., cov: 23)
Exomes 𝑓: 0.000086 ( 0 hom. 50 hem. )

Consequence

HUWE1
NM_031407.7 splice_region, intron

Scores

2
Splicing: ADA: 0.0001336
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.565

Publications

1 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 -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant X-53548953-C-T is Benign according to our data. Variant chrX-53548953-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191249.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000107 (12/111917) while in subpopulation SAS AF = 0.00461 (12/2602). AF 95% confidence interval is 0.00266. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
BS2
High AC in GnomAd4 at 12 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUWE1NM_031407.7 linkc.10035+6G>A splice_region_variant, intron_variant Intron 67 of 83 ENST00000262854.11 NP_113584.3 Q7Z6Z7-1A0A024R9W5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HUWE1ENST00000262854.11 linkc.10035+6G>A splice_region_variant, intron_variant Intron 67 of 83 1 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1

Frequencies

GnomAD3 genomes
AF:
0.000107
AC:
12
AN:
111865
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00459
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000204
AC:
29
AN:
142033
AF XY:
0.000347
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000260
GnomAD4 exome
AF:
0.0000856
AC:
92
AN:
1075047
Hom.:
0
Cov.:
31
AF XY:
0.000143
AC XY:
50
AN XY:
349553
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25817
American (AMR)
AF:
0.00
AC:
0
AN:
31610
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18956
East Asian (EAS)
AF:
0.00
AC:
0
AN:
28963
South Asian (SAS)
AF:
0.00163
AC:
84
AN:
51492
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
39240
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3943
European-Non Finnish (NFE)
AF:
0.00000121
AC:
1
AN:
829701
Other (OTH)
AF:
0.000154
AC:
7
AN:
45325
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome 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
GnomAD4 genome
AF:
0.000107
AC:
12
AN:
111917
Hom.:
0
Cov.:
23
AF XY:
0.000176
AC XY:
6
AN XY:
34107
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30823
American (AMR)
AF:
0.00
AC:
0
AN:
10618
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2652
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3559
South Asian (SAS)
AF:
0.00461
AC:
12
AN:
2602
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6112
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
218
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53124
Other (OTH)
AF:
0.00
AC:
0
AN:
1524
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.00
Hom.:
0
Bravo
AF:
0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 28, 2016
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

not provided Benign:1
Feb 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.50
CADD
Benign
12
DANN
Benign
0.56
PhyloP100
0.56
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00013
dbscSNV1_RF
Benign
0.040
SpliceAI score (max)
0.0
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: rs782009073; hg19: chrX-53575914; API