1-236835586-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000254.3(MTR):โc.1228G>Cโ(p.Ala410Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000254.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000670 AC: 1AN: 149354Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 genome AF: 0.00000670 AC: 1AN: 149354Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 72680
ClinVar
Submissions by phenotype
Methylcobalamin deficiency type cblG Pathogenic:1
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Methylcobalamin deficiency type cblG;C1866558:Neural tube defects, folate-sensitive Pathogenic:1
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not specified Uncertain:1
Variant summary: MTR c.1228G>C (p.Ala410Pro) results in a non-conservative amino acid change located in the Pterin-binding domain (IPR000489) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1228G>C has been reported in the literature in an individual affected with Methylcobalamin deficiency type cblG (Watkins_2002). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12068375). ClinVar contains an entry for this variant (Variation ID: 14288). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at