chr14-77555401-C-T

Position:

• chr14-77555401-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

The NM_004863.4(SPTLC2):​c.1075G>A​(p.Val359Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,894 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SPTLC2 NM_004863.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.80

Genes affected

SPTLC2 (HGNC:11278): (serine palmitoyltransferase long chain base subunit 2) This gene encodes a long chain base subunit of serine palmitoyltransferase. Serine palmitoyltransferase, which consists of two different subunits, is the key enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine. Mutations in this gene were identified in patients with hereditary sensory neuropathy type I. [provided by RefSeq, Mar 2011]

SPTLC2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 14-77555401-C-T is Pathogenic according to our data. Variant chr14-77555401-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4798.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr14-77555401-C-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.1075G>A	p.Val359Met	missense_variant	8/12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3	c.1075G>A	p.Val359Met	missense_variant	8/10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.1075G>A	p.Val359Met	missense_variant	8/12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1C Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 08, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 359 of the SPTLC2 protein (p.Val359Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 20920666). ClinVar contains an entry for this variant (Variation ID: 4798). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPTLC2 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SPTLC2 function (PMID: 20920666, 24175284, 26681808). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.60		Gain of catalytic residue at T355 (P = 4e-04);
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267607090; hg19: chr14-78021744;