chr14-77518097-T-A

Variant names:

• chr14-77518097-T-A
• rs267607091
• NM_004863.4:c.1510A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004863.4(SPTLC2):​c.1510A>T​(p.Ile504Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I504T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTLC2 NM_004863.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• 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, 0.814
• PP5: Variant 14-77518097-T-A is Pathogenic according to our data. Variant chr14-77518097-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 4799.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.1510A>T	p.Ile504Phe	missense_variant	Exon 11 of 12	ENST00000216484.7	NP_004854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.1510A>T	p.Ile504Phe	missense_variant	Exon 11 of 12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC, SEVERE Pathogenic:1

Oct 08, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.051
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.70
Sift	Benign	0.084	T
Sift4G	Benign	0.23	T
Polyphen		0.17	B
Vest4		0.90
MutPred		0.52		Gain of catalytic residue at I504 (P = 0);
MVP		0.92
MPC		0.94
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.91
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs267607091; hg19: chr14-77984440;