6-49451690-T-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong
The NM_000255.4(MMUT):c.1108A>C(p.Thr370Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,170 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_000255.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MMUT | NM_000255.4 | c.1108A>C | p.Thr370Pro | missense_variant | Exon 6 of 13 | ENST00000274813.4 | NP_000246.2 | |
MMUT | XM_005249143.4 | c.1108A>C | p.Thr370Pro | missense_variant | Exon 6 of 13 | XP_005249200.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250768Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135540
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 370 of the MUT protein (p.Thr370Pro). This variant is present in population databases (rs368790885, gnomAD 0.01%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 16281286; Invitae). ClinVar contains an entry for this variant (Variation ID: 203847). 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 expected to disrupt MUT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
The T370P missense variant in the MUT gene has been reported previously in association with methylmalonic acidemia (MMA) (Worgan et al., 2006). The T370P variant was identified on 2/58 (3.4%) MUT alleles in patients of African ancestry with MMA (Worgan et al., 2006). Based on currently available evidence, T370P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at