rs2247856

chr17-76385474-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000323374.8(SPHK1):c.88G>A(p.Ala30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,556,998 control chromosomes in the GnomAD database, including 148,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (10417 hom., cov: 33)
  • Exomes 𝑓: 0.43 (137683 hom.)
• Consequence: SPHK1 ENST00000323374.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.532199E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPHK1	NM_001142601.2	c.-171G>A		5_prime_UTR_variant	2/6	ENST00000592299.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPHK1	ENST00000592299.6	c.-171G>A		5_prime_UTR_variant	2/6	1	NM_001142601.2	P2

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51121 AN: 152012 Hom.: 10425 Cov.: 33

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.399 AC: 66239 AN: 166032 Hom.: 14076 AF XY: 0.396 AC XY: 36478 AN XY: 92148

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.324

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.435 AC: 610761 AN: 1404868 Hom.: 137683 Cov.: 59 AF XY: 0.432 AC XY: 300168 AN XY: 695512

Gnomad4 AFR exome AF: 0.0786

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.446

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.404

GnomAD4 genome AF: 0.336 AC: 51112 AN: 152130 Hom.: 10417 Cov.: 33 AF XY: 0.335 AC XY: 24904 AN XY: 74378

Gnomad4 AFR AF: 0.0922

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.338

Alfa AF: 0.427 Hom.: 11032

Bravo AF: 0.321

TwinsUK AF: 0.472 AC: 1750

ALSPAC AF: 0.473 AC: 1822

ESP6500AA AF: 0.0822 AC: 269

ESP6500EA AF: 0.411 AC: 2929

ExAC AF: 0.350 AC: 39119

Asia WGS AF: 0.281 AC: 978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	13
Dann	Uncertain	1.0
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.000065	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.013
Sift	Benign	0.034	D
Sift4G	Uncertain	0.044	D
Polyphen		0.025	B
Vest4		0.031
MPC		0.29
ClinPred		0.0042	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2247856; hg19: chr17-74381555; COSMIC: COSV60059629; COSMIC: COSV60059629;