rs2247856

Variant names:

• chr17-76385474-G-A
• rs2247856
• ENST00000323374.8:c.88G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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
• Publications: 24 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 -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 rank	MANE	Protein	UniProt
SPHK1	NM_001142601.2	c.-171G>A		5_prime_UTR_variant	Exon 2 of 6	ENST00000592299.6	NP_001136073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPHK1	ENST00000592299.6	c.-171G>A		5_prime_UTR_variant	Exon 2 of 6	1	NM_001142601.2	ENSP00000465726.2

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

GnomAD2 exomes AF: 0.399 AC: 66239 AN: 166032 AF XY: 0.396

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 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

African (AFR) AF: 0.0786 AC: 2536 AN: 32282

American (AMR) AF: 0.440 AC: 17376 AN: 39476

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 9740 AN: 25314

East Asian (EAS) AF: 0.208 AC: 7790 AN: 37430

South Asian (SAS) AF: 0.315 AC: 25614 AN: 81248

European-Finnish (FIN) AF: 0.446 AC: 15780 AN: 35356

Middle Eastern (MID) AF: 0.322 AC: 1319 AN: 4098

European-Non Finnish (NFE) AF: 0.465 AC: 507022 AN: 1091312

Other (OTH) AF: 0.404 AC: 23584 AN: 58352

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

African (AFR) AF: 0.0922 AC: 3832 AN: 41554

American (AMR) AF: 0.399 AC: 6106 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3466

East Asian (EAS) AF: 0.220 AC: 1135 AN: 5156

South Asian (SAS) AF: 0.314 AC: 1516 AN: 4828

European-Finnish (FIN) AF: 0.447 AC: 4724 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31261 AN: 67954

Other (OTH) AF: 0.338 AC: 711 AN: 2106

Alfa AF: 0.416 Hom.: 17592

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
AlphaMissense	Benign	0.084
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
PhyloP100		-0.18
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
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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