rs138268337

chr9-92050073-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006415.4(SPTLC1):c.781-6A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,563,122 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.016 (229 hom.)
• Consequence: SPTLC1 NM_006415.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001447
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.197

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-92050073-T-C is Benign according to our data. Variant chr9-92050073-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 139322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92050073-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0127 (1928/151822) while in subpopulation AMR AF= 0.0204 (312/15294). AF 95% confidence interval is 0.0185. There are 23 homozygotes in gnomad4. There are 878 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1929 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTLC1	NM_006415.4	c.781-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262554.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTLC1	ENST00000262554.7	c.781-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006415.4	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1929 AN: 151704 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00332

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0126 AC: 3164 AN: 250834 Hom.: 36 AF XY: 0.0127 AC XY: 1725 AN XY: 135576

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.00393

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0165 AC: 23250 AN: 1411300 Hom.: 229 Cov.: 24 AF XY: 0.0161 AC XY: 11358 AN XY: 705370

Gnomad4 AFR exome AF: 0.00264

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0127 AC: 1928 AN: 151822 Hom.: 23 Cov.: 32 AF XY: 0.0118 AC XY: 878 AN XY: 74230

Gnomad4 AFR AF: 0.00331

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0161 Hom.: 14

Bravo AF: 0.0137

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0206

EpiControl AF: 0.0226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

SPTLC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuropathy, hereditary sensory and autonomic, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary sensory and autonomic neuropathy type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.3
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138268337; hg19: chr9-94812355;