9-92032287-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006415.4(SPTLC1):c.*178T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000714 in 1,529,302 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: SPTLC1 NM_006415.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.475

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-92032287-A-T is Benign according to our data. Variant chr9-92032287-A-T is described in ClinVar as [Benign]. Clinvar id is 367541.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000887 (135/152132) while in subpopulation AMR AF= 0.00321 (49/15274). AF 95% confidence interval is 0.00249. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTLC1	NM_006415.4	c.*178T>A		3_prime_UTR_variant	15/15	ENST00000262554.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTLC1	ENST00000262554.7	c.*178T>A		3_prime_UTR_variant	15/15	1	NM_006415.4	P1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000839

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000726 AC: 96 AN: 132208 Hom.: 0 AF XY: 0.000618 AC XY: 44 AN XY: 71222

Gnomad AFR exome AF: 0.000599

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.0000924

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.000695 AC: 957 AN: 1377170 Hom.: 2 Cov.: 30 AF XY: 0.000698 AC XY: 474 AN XY: 679152

Gnomad4 AFR exome AF: 0.000609

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.000120

Gnomad4 EAS exome AF: 0.0000841

Gnomad4 SAS exome AF: 0.000281

Gnomad4 FIN exome AF: 0.0000292

Gnomad4 NFE exome AF: 0.000726

Gnomad4 OTH exome AF: 0.000660

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000820 AC XY: 61 AN XY: 74384

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000839

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000918

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.0
Dann	Benign	0.42

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: rs184220566; hg19: chr9-94794569; COSMIC: COSV52766032; COSMIC: COSV52766032;