19-34438643-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_005499.3(UBA2):c.460-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
UBA2
NM_005499.3 splice_acceptor
NM_005499.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.78
Genes affected
UBA2 (HGNC:30661): (ubiquitin like modifier activating enzyme 2) Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1; MIM 601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 (MIM 613294) and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999 [PubMed 9920803]).[supplied by OMIM, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 19-34438643-A-G is Pathogenic according to our data. Variant chr19-34438643-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3064270.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBA2 | NM_005499.3 | c.460-2A>G | splice_acceptor_variant | ENST00000246548.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBA2 | ENST00000246548.9 | c.460-2A>G | splice_acceptor_variant | 1 | NM_005499.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ACCES syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Laboratory, Etlik City Hospital | Mar 25, 2024 | The whole-exome sequencing (WES) analysis of the patient, who presented with a phenotype resembling spondyloepiphyseal dysplasia tarda, revealed a heterozygous variant, NM_005499.3:c.460-2A>G, in the UBA2 gene. This variant has not been previously documented in the medical literature or major variant databases such as ClinVar or LOVD, and it is absent in population data from GnomAD. Located at the canonical acceptor splice site, precisely at the junction of intron 5 and exon 6 in the NM_005499.2 transcript, which comprises a total of 17 exons, it is anticipated that this variant will affect the splicing process. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, the c.460-2A>G variant is classified as pathogenic (Richards et al., 2015). The WES analysis did not identify any additional variants classified as pathogenic or likely pathogenic. Consequently, the identified variant was interpreted as clinically relevant within the spectrum of UBA2-related conditions. The father, affected by a similar phenotype, carried the variant in the heterozygous state, consistent with his daughter's genetic makeup. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.