chrX-53550683-ACCC-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS2

The NM_031407.7(HUWE1):​c.9468_9470delGGG​(p.Gly3157del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000174 in 1,208,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)
Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

HUWE1
NM_031407.7 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.15

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: Likely_benign. The variant received -4 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_031407.7. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant X-53550683-ACCC-A is Benign according to our data. Variant chrX-53550683-ACCC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211171.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 18 XL,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUWE1NM_031407.7 linkc.9468_9470delGGG p.Gly3157del disruptive_inframe_deletion Exon 66 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.9468_9470delGGG p.Gly3157del disruptive_inframe_deletion Exon 66 of 84 1 NM_031407.7 ENSP00000262854.6 Q7Z6Z7-1
HUWE1ENST00000342160.7 linkc.9468_9470delGGG p.Gly3157del disruptive_inframe_deletion Exon 65 of 83 5 ENSP00000340648.3 Q7Z6Z7-1
HUWE1ENST00000612484.4 linkc.9441_9443delGGG p.Gly3148del disruptive_inframe_deletion Exon 63 of 81 5 ENSP00000479451.1 Q7Z6Z7-3
HUWE1ENST00000704099.1 linkc.9465_9467delGGG p.Gly3156del disruptive_inframe_deletion Exon 65 of 83 ENSP00000515693.1 A0A994J483

Frequencies

GnomAD3 genomes
AF:
0.0000271
AC:
3
AN:
110895
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000959
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:
0.0000378
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000273
AC:
5
AN:
183091
AF XY:
0.0000148
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:
0.0000612
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
18
AN:
1097265
Hom.:
0
AF XY:
0.0000165
AC XY:
6
AN XY:
362653
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26386
American (AMR)
AF:
0.0000284
AC:
1
AN:
35202
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54118
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40520
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4092
European-Non Finnish (NFE)
AF:
0.0000178
AC:
15
AN:
841320
Other (OTH)
AF:
0.0000434
AC:
2
AN:
46043
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
3
4
5
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:
0.0000271
AC:
3
AN:
110895
Hom.:
0
Cov.:
22
AF XY:
0.0000603
AC XY:
2
AN XY:
33161
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30433
American (AMR)
AF:
0.0000959
AC:
1
AN:
10426
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2648
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3536
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2616
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5923
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
237
European-Non Finnish (NFE)
AF:
0.0000378
AC:
2
AN:
52905
Other (OTH)
AF:
0.00
AC:
0
AN:
1483
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

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:
0.0000868
Hom.:
0
Bravo
AF:
0.0000907

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Oct 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.9468_9470del, results in the deletion of 1 amino acid(s) of the HUWE1 protein (p.Gly3157del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs782375893, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with HUWE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 211171). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1
Dec 18, 2014
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Nov 15, 2024
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
5.2
Mutation Taster
=84/16
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs782375893; hg19: chrX-53577644; API