9-92077060-A-G

Variant names:

• chr9-92077060-A-G
• rs7856177
• NM_006415.4:c.427+2956T>C

Variant summary

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

The NM_006415.4(SPTLC1):​c.427+2956T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 151,886 control chromosomes in the GnomAD database, including 11,773 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 0.33 (11768 hom., cov: 31)
  • Exomes 𝑓: 0.24 (5 hom.)
• Consequence: SPTLC1 NM_006415.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 4 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	NM_006415.4	MANE Select	c.427+2956T>C		intron	N/A	NP_006406.1
	SPTLC1	NM_001281303.2		c.427+2956T>C		intron	N/A	NP_001268232.1
	SPTLC1	NM_001368272.1		c.61+2374T>C		intron	N/A	NP_001355201.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.427+2956T>C		intron	N/A	ENSP00000262554.2
	SPTLC1	ENST00000686600.1		c.427+2956T>C		intron	N/A	ENSP00000509268.1
	SPTLC1	ENST00000687972.1		c.427+2956T>C		intron	N/A	ENSP00000509208.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49787 AN: 151696 Hom.: 11732 Cov.: 31

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.243 AC: 17 AN: 70 Hom.: 5 Cov.: 0 AF XY: 0.180 AC XY: 9 AN XY: 50

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 1.00 AC: 8 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.104 AC: 5 AN: 48

Other (OTH) AF: 0.167 AC: 1 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0712069), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.329 AC: 49882 AN: 151816 Hom.: 11768 Cov.: 31 AF XY: 0.329 AC XY: 24424 AN XY: 74200

African (AFR) AF: 0.659 AC: 27255 AN: 41342

American (AMR) AF: 0.330 AC: 5040 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3468

East Asian (EAS) AF: 0.367 AC: 1883 AN: 5134

South Asian (SAS) AF: 0.263 AC: 1263 AN: 4806

European-Finnish (FIN) AF: 0.192 AC: 2027 AN: 10546

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10635 AN: 67944

Other (OTH) AF: 0.301 AC: 633 AN: 2106

Alfa AF: 0.207 Hom.: 2251

Bravo AF: 0.353

Asia WGS AF: 0.357 AC: 1243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-1.1
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: rs7856177; hg19: chr9-94839342;