rs72554356
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000531.6(OTC):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,175,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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OTC | NM_000531.6 | c.374C>T | p.Thr125Met | missense_variant | Exon 4 of 10 | ENST00000039007.5 | NP_000522.3 | |
OTC | NM_001407092.1 | c.374C>T | p.Thr125Met | missense_variant | Exon 6 of 12 | NP_001394021.1 | ||
OTC | XM_017029556.2 | c.374C>T | p.Thr125Met | missense_variant | Exon 4 of 9 | XP_016885045.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000898 AC: 1AN: 111307Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1AN XY: 33531
GnomAD3 exomes AF: 0.0000110 AC: 2AN: 182605Hom.: 0 AF XY: 0.0000298 AC XY: 2AN XY: 67159
GnomAD4 exome AF: 0.0000160 AC: 17AN: 1063696Hom.: 0 Cov.: 26 AF XY: 0.0000331 AC XY: 11AN XY: 332178
GnomAD4 genome AF: 0.00000898 AC: 1AN: 111360Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1AN XY: 33594
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Uncertain:4
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The missense variant c.374C>T (p.Thr125Met) in OTC has been submitted to ClinVar as a Variant of Uncertain Significance. This variant has been observed in an individual affected with OTC deficiency (Gilbert-Dussardier B et al). Experimental studies have shown that this missense change causes lack of OTC enzymatic activity in vitro (Suriano G et al) This p.Thr125Met variant has allele frequency of 0.001095% in the gnomAD and novel (not in any individuals) in 1000 genome database. The amino acid Thr at position 125 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
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This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the OTC protein (p.Thr125Met). This variant is present in population databases (rs72554356, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with OTC deficiency (PMID: 8807340). ClinVar contains an entry for this variant (Variation ID: 97175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OTC protein function. Experimental studies have shown that this missense change affects OTC function (PMID: 17613537). 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 provided Pathogenic:1Uncertain:2
Published functional studies demonstrate that the T125M variant has reduced activity compared to wild type (Suriano et al., 2007); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with OTC deficiency by enzyme results, however full sequencing of OTC gene was not performed (Gilbert-Dussardier et al., 1996); This variant is associated with the following publications: (PMID: 17613537, 25637381, 27703146, 8807340, 28324312, 9452049) -
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not specified Uncertain:1
Variant summary: OTC c.374C>T (p.Thr125Met) results in a non-conservative amino acid change located in the carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 182605 control chromosomes, including 2 hemizygotes, suggesting the variant may be benign. c.374C>T has been reported in the literature as a hemizygous genotype in at least one individual affected with neonatal onset Ornithine Transcarbamylase Deficiency who also had two unaffected female relatives who carried the variant, however X-inactivation pattern was not reported in these individuals (e.g. Gilbert-Dussardier_1996, Gobin-Limballe_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in little to no enzyme activity compared to the WT protein (Suriano_2007). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 8807340, 34014569, 17613537). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Hyperammonemia Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at