9-92032341-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: -0.874

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 367542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92032341-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 947 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTLC1	NM_006415.4	c.*124A>G		3_prime_UTR_variant	15/15	ENST00000262554.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTLC1	ENST00000262554.7	c.*124A>G		3_prime_UTR_variant	15/15	1	NM_006415.4	P1

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

GnomAD3 exomes AF: 0.00477 AC: 847 AN: 177666 Hom.: 5 AF XY: 0.00473 AC XY: 452 AN XY: 95476

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00942

Gnomad4 NFE exome AF: 0.00807

Gnomad4 OTH exome AF: 0.00640

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

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00454 Hom.: 2

Bravo AF: 0.00635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SPTLC1: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Neuropathy, hereditary sensory and autonomic, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.41
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

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