rs139083778
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000254.3(MTR):c.13C>A(p.Leu5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000254.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152284Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251196Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135876
GnomAD4 exome AF: 0.000145 AC: 212AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98AN XY: 727206
GnomAD4 genome AF: 0.000151 AC: 23AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74398
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.13C>A (p.L5I) alteration is located in exon 1 (coding exon 1) of the MTR gene. This alteration results from a C to A substitution at nucleotide position 13, causing the leucine (L) at amino acid position 5 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Methylcobalamin deficiency type cblG Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5 of the MTR protein (p.Leu5Ile). This variant is present in population databases (rs139083778, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1352967). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at