rs200704785

chr9-92038238-G-Achr9-92038238-G-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.1254+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,565,952 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (50 hom.)
• Consequence: SPTLC1 NM_006415.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.725

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=-0.85).
• BP6: Variant 9-92038238-G-A is Benign according to our data. Variant chr9-92038238-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 367544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000936 (142/151772) while in subpopulation SAS AF= 0.0276 (133/4826). AF 95% confidence interval is 0.0237. There are 3 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTLC1	NM_006415.4	c.1254+10C>T		intron_variant		ENST00000262554.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTLC1	ENST00000262554.7	c.1254+10C>T		intron_variant		1	NM_006415.4	P1

Frequencies

GnomAD3 genomes AF: 0.000936 AC: 142 AN: 151654 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00378 AC: 951 AN: 251476 Hom.: 18 AF XY: 0.00516 AC XY: 701 AN XY: 135916

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0304

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00180 AC: 2552 AN: 1414180 Hom.: 50 Cov.: 26 AF XY: 0.00266 AC XY: 1881 AN XY: 706248

Gnomad4 AFR exome AF: 0.0000620

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000365

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.000936 AC: 142 AN: 151772 Hom.: 3 Cov.: 32 AF XY: 0.00131 AC XY: 97 AN XY: 74210

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0276

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000193

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary sensory and autonomic neuropathy type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.71
Dann	Benign	0.48

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: rs200704785; hg19: chr9-94800520;