rs1554706531

Variant names:

• chr9-92047678-T-C
• rs1554706531
• NM_006415.4:c.919A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006415.4(SPTLC1):​c.919A>G​(p.Met307Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTLC1 NM_006415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.72
• Publications: 0 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neuropathy, hereditary sensory and autonomic, type 1A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

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.919A>G	p.Met307Val	missense	Exon 10 of 15	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.919A>G	p.Met307Val	missense	Exon 10 of 15	NP_001268232.1
	SPTLC1	NM_001368272.1		c.553A>G	p.Met185Val	missense	Exon 11 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.919A>G	p.Met307Val	missense	Exon 10 of 15	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.1129A>G	p.Met377Val	missense	Exon 11 of 16	ENSP00000623559.1
	SPTLC1	ENST00000884978.1		c.919A>G	p.Met307Val	missense	Exon 10 of 16	ENSP00000555037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461118 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111390

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary sensory and autonomic neuropathy type 1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.018	D
Polyphen		0.13	B
Vest4		0.95
MutPred		0.83		Gain of sheet (P = 0.1945)
MVP		0.85
MPC		0.51
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.95
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: rs1554706531; hg19: chr9-94809960;