rs7863487

Variant names:

• chr9-92034890-G-A
• rs7863487
• NM_006415.4:c.1255-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006415.4(SPTLC1):​c.1255-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,612,444 control chromosomes in the GnomAD database, including 101 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 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (49 hom.)
• Consequence: SPTLC1 NM_006415.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001092
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.588
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-92034890-G-A is Benign according to our data. Variant chr9-92034890-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	NM_006415.4	MANE Select	c.1255-7C>T		splice_region intron	N/A	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.1255-7C>T		splice_region intron	N/A	NP_001268232.1
	SPTLC1	NM_001368272.1		c.889-7C>T		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.1255-7C>T		splice_region intron	N/A	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.1465-7C>T		splice_region intron	N/A	ENSP00000623559.1
	SPTLC1	ENST00000884978.1		c.1255-7C>T		splice_region intron	N/A	ENSP00000555037.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2037 AN: 151658 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00380 AC: 954 AN: 251374 AF XY: 0.00284

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00163 AC: 2378 AN: 1460668 Hom.: 49 Cov.: 30 AF XY: 0.00149 AC XY: 1085 AN XY: 726748

African (AFR) AF: 0.0526 AC: 1743 AN: 33136

American (AMR) AF: 0.00356 AC: 159 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1111260

Other (OTH) AF: 0.00383 AC: 231 AN: 60328

GnomAD4 genome AF: 0.0135 AC: 2045 AN: 151776 Hom.: 52 Cov.: 33 AF XY: 0.0126 AC XY: 933 AN XY: 74192

African (AFR) AF: 0.0461 AC: 1893 AN: 41084

American (AMR) AF: 0.00648 AC: 99 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.00799 Hom.: 11

Bravo AF: 0.0159

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.26
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.010
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: rs7863487; hg19: chr9-94797172;