rs138268337

Variant names:

• chr9-92050073-T-C
• rs138268337
• NM_006415.4:c.781-6A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0001447
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.197
• Publications: 3 publications found

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]

SPTLC1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis 27, juvenile

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neuropathy, hereditary sensory and autonomic, type 1A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 139322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1928 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	NM_006415.4	MANE Select	c.781-6A>G		splice_region intron	N/A	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.781-6A>G		splice_region intron	N/A	NP_001268232.1
	SPTLC1	NM_001368272.1		c.415-6A>G		splice_region intron	N/A	NP_001355201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.781-6A>G		splice_region intron	N/A	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.991-6A>G		splice_region intron	N/A	ENSP00000623559.1
	SPTLC1	ENST00000884978.1		c.781-6A>G		splice_region intron	N/A	ENSP00000555037.1

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

GnomAD2 exomes AF: 0.0126 AC: 3164 AN: 250834 AF XY: 0.0127

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 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

African (AFR) AF: 0.00264 AC: 85 AN: 32240

American (AMR) AF: 0.0114 AC: 510 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 628 AN: 25818

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39462

South Asian (SAS) AF: 0.00285 AC: 243 AN: 85212

European-Finnish (FIN) AF: 0.00431 AC: 230 AN: 53370

Middle Eastern (MID) AF: 0.0194 AC: 110 AN: 5672

European-Non Finnish (NFE) AF: 0.0193 AC: 20602 AN: 1066220

Other (OTH) AF: 0.0143 AC: 838 AN: 58656

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

African (AFR) AF: 0.00331 AC: 136 AN: 41082

American (AMR) AF: 0.0204 AC: 312 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1268 AN: 68018

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Hereditary sensory and autonomic neuropathy type 1 (1)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 1A (1)
-	-	1	SPTLC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.3
DANN	Benign	0.74
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs138268337; hg19: chr9-94812355;