rs532178791
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The ENST00000494238.6(UBA5):āc.1A>Gā(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 32)
Exomes š: 0.000025 ( 0 hom. )
Consequence
UBA5
ENST00000494238.6 start_lost
ENST00000494238.6 start_lost
Scores
5
9
3
Clinical Significance
Conservation
PhyloP100: 9.02
Genes affected
UBA5 (HGNC:23230): (ubiquitin like modifier activating enzyme 5) This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1. [provided by RefSeq, Feb 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in ENST00000494238.6 (UBA5) was described as [Pathogenic] in Lovd
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-132665830-A-G is Pathogenic according to our data. Variant chr3-132665830-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265755.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UBA5 | NM_024818.6 | c.169A>G | p.Met57Val | missense_variant | 2/12 | ENST00000356232.10 | |
NPHP3-ACAD11 | NR_037804.1 | n.3995+16084T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UBA5 | ENST00000356232.10 | c.169A>G | p.Met57Val | missense_variant | 2/12 | 1 | NM_024818.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152050Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
7
AN:
152050
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 251066Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135710
GnomAD3 exomes
AF:
AC:
25
AN:
251066
Hom.:
AF XY:
AC XY:
18
AN XY:
135710
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460980Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 726786
GnomAD4 exome
AF:
AC:
37
AN:
1460980
Hom.:
Cov.:
31
AF XY:
AC XY:
23
AN XY:
726786
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74418
GnomAD4 genome
?
AF:
AC:
6
AN:
152172
Hom.:
Cov.:
32
AF XY:
AC XY:
5
AN XY:
74418
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
10
Asia WGS
AF:
AC:
3
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 44 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27545681 , 27545681 , 27926783). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90). The variant has been previously reported to be associated with UBA5-related disorder (PMID: 27545681). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 27545681 , 27926783). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 10, 2020 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 57 of the UBA5 protein (p.Met57Val). This variant is present in population databases (rs532178791, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of UBA5-related conditions (PMID: 27545681). ClinVar contains an entry for this variant (Variation ID: 265755). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects UBA5 function (PMID: 27545681, 29663568). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2022 | Published functional studies demonstrate drastic reductions in catalytic activities (Colin E et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27545681, 27926783, 30078785) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;T;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
0.94
.;P;.;.;P;.;.
Vest4
MutPred
0.56
.;Gain of glycosylation at Y53 (P = 0.0136);Gain of glycosylation at Y53 (P = 0.0136);.;Gain of glycosylation at Y53 (P = 0.0136);.;.;
MVP
MPC
0.31
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at