NM_001142601.2:c.433C>T

Variant names:

• chr17-76386864-C-T
• rs1045698072
• NM_001142601.2:c.433C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001142601.2(SPHK1):​c.433C>T​(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPHK1 NM_001142601.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142601.2. 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.433C>T	p.Arg145Trp	missense	Exon 6 of 6	NP_001136073.1	Q9NYA1-1
	SPHK1	NM_182965.3		c.691C>T	p.Arg231Trp	missense	Exon 6 of 6	NP_892010.2	Q9NYA1-2
	SPHK1	NM_021972.4		c.475C>T	p.Arg159Trp	missense	Exon 6 of 6	NP_068807.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHK1	ENST00000592299.6	TSL:1 MANE Select	c.433C>T	p.Arg145Trp	missense	Exon 6 of 6	ENSP00000465726.2	Q9NYA1-1
	SPHK1	ENST00000323374.8	TSL:1	c.691C>T	p.Arg231Trp	missense	Exon 6 of 6	ENSP00000313681.3	Q9NYA1-2
	SPHK1	ENST00000590959.5	TSL:1	c.475C>T	p.Arg159Trp	missense	Exon 6 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 244182 AF XY: 0.00000758

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448332 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718708

African (AFR) AF: 0.0000301 AC: 1 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 43634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.00 AC: 0 AN: 84868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103938

Other (OTH) AF: 0.00 AC: 0 AN: 59766

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.62		Gain of sheet (P = 0.0266)
MVP		0.71
MPC		0.35
ClinPred		0.26	T
GERP RS		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
Mutation Taster		=75/25	polymorphism

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: rs1045698072; hg19: chr17-74382945;