rs532178791
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_198329.4(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
NM_198329.4 start_lost
NM_198329.4 start_lost
Scores
6
9
4
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]
NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]
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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 NM_198329.4 (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: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
UBA5 | NM_024818.6 | c.169A>G | p.Met57Val | missense_variant | 2/12 | ENST00000356232.10 | NP_079094.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
UBA5 | ENST00000356232.10 | c.169A>G | p.Met57Val | missense_variant | 2/12 | 1 | NM_024818.6 | ENSP00000348565.4 | ||
NPHP3-ACAD11 | ENST00000632629.1 | c.635+16084T>C | intron_variant | 2 | ENSP00000488520.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152050Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000996 AC: 25AN: 251066Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135710
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460980Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 726786
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74418
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 44 Pathogenic:2Uncertain:2
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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 18, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 10, 2020 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2024 | Published functional studies demonstrate a damaging effect: drastic reductions in catalytic activities and decreased ATP binding (PMID: 27545681, 38079206); 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: 27926783, 30078785, 36932998, 35672414, 36680403, 38079206, 27545681) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.;.;.
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
MutationAssessor
Pathogenic
.;M;.;.;.;.;.
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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at