ENST00000323374.8:c.95C>T

Variant names:

• chr17-76385481-C-T
• rs201987985
• ENST00000323374.8:c.95C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000323374.8(SPHK1):​c.95C>T​(p.Ala32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,408,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SPHK1 ENST00000323374.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.67
• Publications: 4 publications found

Genes affected

SPHK1 (HGNC:11240): (sphingosine kinase 1) The protein encoded by this gene catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), a lipid mediator with both intra- and extracellular functions. Intracellularly, S1P regulates proliferation and survival, and extracellularly, it is a ligand for cell surface G protein-coupled receptors. This protein, and its product S1P, play a key role in TNF-alpha signaling and the NF-kappa-B activation pathway important in inflammatory, antiapoptotic, and immune processes. Phosphorylation of this protein alters its catalytic activity and promotes its translocation to the plasma membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039594233).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323374.8. 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
	SPHK1	NM_001142601.2	MANE Select	c.-164C>T		5_prime_UTR	Exon 2 of 6	NP_001136073.1	Q9NYA1-1
	SPHK1	NM_182965.3		c.95C>T	p.Ala32Val	missense	Exon 2 of 6	NP_892010.2	Q9NYA1-2
	SPHK1	NM_021972.4		c.-164C>T		5_prime_UTR	Exon 2 of 6	NP_068807.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHK1	ENST00000323374.8	TSL:1	c.95C>T	p.Ala32Val	missense	Exon 2 of 6	ENSP00000313681.3	Q9NYA1-2
	SPHK1	ENST00000592299.6	TSL:1 MANE Select	c.-164C>T		5_prime_UTR	Exon 2 of 6	ENSP00000465726.2	Q9NYA1-1
	SPHK1	ENST00000590959.5	TSL:1	c.-164C>T		5_prime_UTR	Exon 2 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000119 AC: 2 AN: 168766 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000217

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1408030 Hom.: 0 Cov.: 60 AF XY: 0.00000430 AC XY: 3 AN XY: 697358

African (AFR) AF: 0.00 AC: 0 AN: 32394

American (AMR) AF: 0.00 AC: 0 AN: 40118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 81404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093032

Other (OTH) AF: 0.0000513 AC: 3 AN: 58536

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000878 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Uncertain	0.99
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.026
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.071
MutPred		0.13		Gain of catalytic residue at A32 (P = 0.0813)
MVP		0.061
MPC		0.60
ClinPred		0.052	T
GERP RS		-2.6
PromoterAI		0.080	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201987985; hg19: chr17-74381562;