NM_006415.4:c.561-556T>G

Variant names:

• chr9-92059864-A-C
• rs7858659
• NM_006415.4:c.561-556T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006415.4(SPTLC1):​c.561-556T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 151,970 control chromosomes in the GnomAD database, including 9,134 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (9134 hom., cov: 31)
• Consequence: SPTLC1 NM_006415.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.05
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC1	NM_006415.4	c.561-556T>G		intron_variant	Intron 6 of 14	ENST00000262554.7	NP_006406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7	c.561-556T>G		intron_variant	Intron 6 of 14	1	NM_006415.4	ENSP00000262554.2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43200 AN: 151852 Hom.: 9116 Cov.: 31

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.285 AC: 43259 AN: 151970 Hom.: 9134 Cov.: 31 AF XY: 0.286 AC XY: 21237 AN XY: 74272

African (AFR) AF: 0.589 AC: 24407 AN: 41454

American (AMR) AF: 0.299 AC: 4564 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 873 AN: 3472

East Asian (EAS) AF: 0.305 AC: 1574 AN: 5156

South Asian (SAS) AF: 0.154 AC: 742 AN: 4804

European-Finnish (FIN) AF: 0.178 AC: 1883 AN: 10580

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8497 AN: 67910

Other (OTH) AF: 0.253 AC: 534 AN: 2112

Alfa AF: 0.182 Hom.: 4723

Bravo AF: 0.308

Asia WGS AF: 0.270 AC: 940 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.16
DANN	Benign	0.53
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7858659; hg19: chr9-94822146;