chr5-110739129-C-CGT
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_138773.4(SLC25A46):c.11_12insTG(p.Arg5GlyfsTer40) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000129 in 1,547,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_138773.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC25A46 | NM_138773.4 | c.11_12insTG | p.Arg5GlyfsTer40 | frameshift_variant | Exon 1 of 8 | ENST00000355943.8 | NP_620128.1 | |
SLC25A46 | NM_001303249.3 | c.11_12insTG | p.Arg5GlyfsTer40 | frameshift_variant | Exon 1 of 8 | NP_001290178.1 | ||
SLC25A46 | NM_001303250.3 | c.10+883_10+884insTG | intron_variant | Intron 1 of 7 | NP_001290179.1 | |||
SLC25A46 | NR_138151.2 | n.124_125insTG | non_coding_transcript_exon_variant | Exon 1 of 9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC25A46 | ENST00000355943.8 | c.11_12insTG | p.Arg5GlyfsTer40 | frameshift_variant | Exon 1 of 8 | 1 | NM_138773.4 | ENSP00000348211.3 | ||
SLC25A46 | ENST00000447245.6 | c.11_12insTG | p.Arg5GlyfsTer40 | frameshift_variant | Exon 1 of 8 | 2 | ENSP00000399717.2 | |||
SLC25A46 | ENST00000513807.5 | c.-204+883_-204+884insTG | intron_variant | Intron 1 of 7 | 2 | ENSP00000421134.1 | ||||
SLC25A46 | ENST00000508781.5 | n.112+883_112+884insTG | intron_variant | Intron 1 of 7 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD4 exome AF: 7.17e-7 AC: 1AN: 1395380Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1AN XY: 688300
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Neuropathy, hereditary motor and sensory, type 6B Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg5Glyfs*40) in the SLC25A46 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A46 are known to be pathogenic (PMID: 26168012, 26951855, 27543974). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 422422). This variant has not been reported in the literature in individuals affected with SLC25A46-related conditions. This variant is not present in population databases (gnomAD no frequency). -
Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E Pathogenic:1
The SLC25A46 c.11_12insTG (p.Arg5GlyfsTer40) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The variant causes a frameshift by inserting two nucleotides, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant has been reported in the ClinVar database as a pathogenic variant by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.11_12insTG pathogenic mutation, located in coding exon 1 of the SLC25A46 gene, results from an insertion of two nucleotides at position 11, causing a translational frameshift with a predicted alternate stop codon (p.R5Gfs*40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
The c.11_12insTG variant in the SLC25A46 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11_12insTG variant causes a frameshift starting with codon Arginine 5, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Arg5GlyfsX40. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11_12insTG variant was not observed in approximately 5800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.11_12insTG as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at