chr17-76386117-C-T

Variant names:

• chr17-76386117-C-T
• rs201349077
• NM_001142601.2:c.143C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142601.2(SPHK1):​c.143C>T​(p.Ser48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000501 in 1,597,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SPHK1 NM_001142601.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.822
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25351465).
• BS2: High AC in GnomAdExome4 at 78 AD gene.

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.143C>T	p.Ser48Phe	missense	Exon 3 of 6	NP_001136073.1	Q9NYA1-1
	SPHK1	NM_182965.3		c.401C>T	p.Ser134Phe	missense	Exon 3 of 6	NP_892010.2	Q9NYA1-2
	SPHK1	NM_021972.4		c.185C>T	p.Ser62Phe	missense	Exon 3 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.143C>T	p.Ser48Phe	missense	Exon 3 of 6	ENSP00000465726.2	Q9NYA1-1
	SPHK1	ENST00000323374.8	TSL:1	c.401C>T	p.Ser134Phe	missense	Exon 3 of 6	ENSP00000313681.3	Q9NYA1-2
	SPHK1	ENST00000590959.5	TSL:1	c.185C>T	p.Ser62Phe	missense	Exon 3 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000451 AC: 11 AN: 243902 AF XY: 0.0000527

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000547

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 78 AN: 1445018 Hom.: 0 Cov.: 32 AF XY: 0.0000544 AC XY: 39 AN XY: 716588

African (AFR) AF: 0.00 AC: 0 AN: 33170

American (AMR) AF: 0.0000452 AC: 2 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.00 AC: 0 AN: 85930

European-Finnish (FIN) AF: 0.0000624 AC: 3 AN: 48104

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000608 AC: 67 AN: 1102862

Other (OTH) AF: 0.0000670 AC: 4 AN: 59714

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.82
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.075
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.95	P
Vest4		0.25
MVP		0.68
MPC		0.34
ClinPred		0.43	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.70
Mutation Taster		=62/38	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: rs201349077; hg19: chr17-74382198;