9-92032485-C-G

Variant names:

• chr9-92032485-C-G
• rs748723735
• NM_006415.4:c.1402G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006415.4(SPTLC1):​c.1402G>C​(p.Ala468Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTLC1 NM_006415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC1	NM_006415.4	c.1402G>C	p.Ala468Pro	missense_variant	Exon 15 of 15	ENST00000262554.7	NP_006406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7	c.1402G>C	p.Ala468Pro	missense_variant	Exon 15 of 15	1	NM_006415.4	ENSP00000262554.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.58		Loss of MoRF binding (P = 0.0181);
MVP		0.88
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.75
Mutation Taster		=44/56	disease causing

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: rs748723735; hg19: chr9-94794767;