NM_006415.4:c.*124A>G

Variant names:

• chr9-92032341-T-C
• rs189582528
• NM_006415.4:c.*124A>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.*124A>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 0.00691 in 1,563,130 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (36 hom.)
• Consequence: SPTLC1 NM_006415.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.874
• Publications: 5 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=-0.9).
• BP6: Variant 9-92032341-T-C is Benign according to our data. Variant chr9-92032341-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00622 (948/152310) while in subpopulation NFE AF = 0.00783 (533/68038). AF 95% confidence interval is 0.00728. There are 6 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 948 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.*124A>G		3_prime_UTR	Exon 15 of 15	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.1514A>G	p.Lys505Arg	missense	Exon 15 of 15	NP_001268232.1
	SPTLC1	NM_001368272.1		c.*124A>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.*124A>G		3_prime_UTR	Exon 15 of 15	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.*124A>G		3_prime_UTR	Exon 16 of 16	ENSP00000623559.1
	SPTLC1	ENST00000884978.1		c.*124A>G		3_prime_UTR	Exon 16 of 16	ENSP00000555037.1

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 947 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00477 AC: 847 AN: 177666 AF XY: 0.00473

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.0000770

Gnomad FIN exome AF: 0.00909

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00698 AC: 9848 AN: 1410820 Hom.: 36 Cov.: 31 AF XY: 0.00681 AC XY: 4760 AN XY: 698556

African (AFR) AF: 0.00320 AC: 103 AN: 32158

American (AMR) AF: 0.00254 AC: 95 AN: 37388

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 73 AN: 25366

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36842

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81934

European-Finnish (FIN) AF: 0.00942 AC: 405 AN: 43014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00807 AC: 8794 AN: 1089608

Other (OTH) AF: 0.00640 AC: 376 AN: 58778

GnomAD4 genome AF: 0.00622 AC: 948 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00624 AC XY: 465 AN XY: 74462

African (AFR) AF: 0.00380 AC: 158 AN: 41568

American (AMR) AF: 0.00588 AC: 90 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00867 AC: 92 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00783 AC: 533 AN: 68038

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00385 Hom.: 3

Bravo AF: 0.00635

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	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	0.41
DANN	Benign	0.53
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs189582528; hg19: chr9-94794623; COSMIC: COSV52766246; COSMIC: COSV52766246;