19-35295422-C-T
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1
The NM_002361.4(MAG):c.14C>T(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,068 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Likely benign.
Frequency
Consequence
NM_002361.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAG | NM_002361.4 | c.14C>T | p.Thr5Met | missense_variant | Exon 3 of 11 | ENST00000392213.8 | NP_002352.1 | |
MAG | NM_080600.3 | c.14C>T | p.Thr5Met | missense_variant | Exon 3 of 12 | NP_542167.1 | ||
MAG | NM_001199216.2 | c.-85-33C>T | intron_variant | Intron 2 of 10 | NP_001186145.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000920 AC: 140AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000211 AC: 53AN: 251400Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135864
GnomAD4 exome AF: 0.0000766 AC: 112AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727208
GnomAD4 genome AF: 0.000913 AC: 139AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59AN XY: 74442
ClinVar
Submissions by phenotype
not specified Benign:1
Variant summary: MAG c.14C>T (p.Thr5Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251400 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in MAG causing Hereditary Spastic Paraplegia 75 phenotype. To our knowledge, no occurrence of c.14C>T in individuals affected with Hereditary Spastic Paraplegia 75 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 704256). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary spastic paraplegia 75 Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at