rs115637483

Variant names:

• chr9-92031975-T-C
• rs115637483
• NM_006415.4:c.*490A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006415.4(SPTLC1):​c.*490A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 284,266 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: SPTLC1 NM_006415.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.704
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuropathy, hereditary sensory and autonomic, type 1A

  Inheritance: AD Classification: STRONG Submitted by: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-92031975-T-C is Benign according to our data. Variant chr9-92031975-T-C is described in ClinVar as Benign. ClinVar VariationId is 913420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00728 (1109/152298) while in subpopulation AFR AF = 0.0249 (1036/41572). AF 95% confidence interval is 0.0237. There are 9 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1109 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.*490A>G		3_prime_UTR	Exon 15 of 15	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.*338A>G		3_prime_UTR	Exon 15 of 15	NP_001268232.1
	SPTLC1	NM_001368272.1		c.*490A>G		3_prime_UTR	Exon 16 of 16	NP_001355201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.*490A>G		3_prime_UTR	Exon 15 of 15	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.*490A>G		3_prime_UTR	Exon 16 of 16	ENSP00000623559.1
	SPTLC1	ENST00000686600.1		c.*624A>G		3_prime_UTR	Exon 16 of 16	ENSP00000509268.1	A0A8I5KUM4

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152180 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.00115 AC: 152 AN: 131968 Hom.: 1 Cov.: 0 AF XY: 0.00111 AC XY: 74 AN XY: 66588

African (AFR) AF: 0.0213 AC: 98 AN: 4610

American (AMR) AF: 0.00224 AC: 13 AN: 5812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5266

East Asian (EAS) AF: 0.00 AC: 0 AN: 11038

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5674

Middle Eastern (MID) AF: 0.00153 AC: 1 AN: 654

European-Non Finnish (NFE) AF: 0.000118 AC: 10 AN: 85060

Other (OTH) AF: 0.00318 AC: 29 AN: 9122

GnomAD4 genome AF: 0.00728 AC: 1109 AN: 152298 Hom.: 9 Cov.: 32 AF XY: 0.00698 AC XY: 520 AN XY: 74460

African (AFR) AF: 0.0249 AC: 1036 AN: 41572

American (AMR) AF: 0.00340 AC: 52 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00336 Hom.: 4

Bravo AF: 0.00811

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neuropathy, hereditary sensory and autonomic, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.61
DANN	Benign	0.42
PhyloP100		-0.70

Splicing

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

Other links and lift over

dbSNP: rs115637483; hg19: chr9-94794257;