rs779810169
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_006415.4(SPTLC1):c.472A>T(p.Thr158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
SPTLC1
NM_006415.4 missense
NM_006415.4 missense
Scores
1
13
5
Clinical Significance
Conservation
PhyloP100: 3.20
Genes affected
SPTLC1 (HGNC:11277): (serine palmitoyltransferase long chain base subunit 1) This gene encodes a member of the class-II pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is the long chain base subunit 1 of serine palmitoyltransferase. Serine palmitoyltransferase converts L-serine and palmitoyl-CoA to 3-oxosphinganine with pyridoxal 5'-phosphate and is the key enzyme in sphingolipid biosynthesis. Mutations in this gene were identified in patients with hereditary sensory neuropathy type 1. Alternatively spliced variants encoding different isoforms have been identified. Pseudogenes of this gene have been defined on chromosomes 1, 6, 10, and 13. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000171 (25/1461756) while in subpopulation MID AF= 0.000173 (1/5768). AF 95% confidence interval is 0.00008. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTLC1 | NM_006415.4 | c.472A>T | p.Thr158Ser | missense_variant | 6/15 | ENST00000262554.7 | NP_006406.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPTLC1 | ENST00000262554.7 | c.472A>T | p.Thr158Ser | missense_variant | 6/15 | 1 | NM_006415.4 | ENSP00000262554.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251146Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135760
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461756Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727180
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuropathy, hereditary sensory and autonomic, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary sensory and autonomic neuropathy type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 10, 2023 | ClinVar contains an entry for this variant (Variation ID: 576860). This variant has not been reported in the literature in individuals affected with SPTLC1-related conditions. This variant is present in population databases (rs779810169, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 158 of the SPTLC1 protein (p.Thr158Ser). 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 not expected to disrupt SPTLC1 protein function. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.0575);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at