chr9-92047199-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_006415.4(SPTLC1):c.1054G>A(p.Ala352Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A352G) has been classified as Uncertain significance.
Frequency
Consequence
NM_006415.4 missense
Scores
Clinical Significance
Conservation
Publications
- amyotrophic lateral sclerosis 27, juvenileInheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- neuropathy, hereditary sensory and autonomic, type 1AInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- hereditary sensory and autonomic neuropathy type 1Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTLC1 | NM_006415.4 | c.1054G>A | p.Ala352Thr | missense_variant | Exon 11 of 15 | ENST00000262554.7 | NP_006406.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251384 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727198 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary sensory and autonomic neuropathy type 1 Uncertain:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 352 of the SPTLC1 protein (p.Ala352Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant has not been reported in the literature in individuals with SPTLC1-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The observation of one missense substitutions at this codon (p.A352V) in affected individuals suggests that this may be a clinically significant residue (PMID: 21618344, 19651702). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at