ENST00000323374.8:c.100G>A

Variant names:

• chr17-76385486-G-A
• rs346803
• ENST00000323374.8:c.100G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000323374.8(SPHK1):​c.100G>A​(p.Ala34Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,559,412 control chromosomes in the GnomAD database, including 609,864 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.88 (58912 hom., cov: 33)
  • Exomes 𝑓: 0.88 (550952 hom.)
• Consequence: SPHK1 ENST00000323374.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765
• Publications: 29 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=9.704484E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPHK1	NM_001142601.2	c.-159G>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.-159G>A		5_prime_UTR_variant	Exon 2 of 6	1	NM_001142601.2	ENSP00000465726.2

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133643 AN: 152124 Hom.: 58859 Cov.: 33

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.878

Gnomad OTH AF: 0.883

GnomAD2 exomes AF: 0.908 AC: 153505 AN: 169066 AF XY: 0.907

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.924

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.884 AC: 1244521 AN: 1407170 Hom.: 550952 Cov.: 76 AF XY: 0.887 AC XY: 617795 AN XY: 696840

African (AFR) AF: 0.834 AC: 27000 AN: 32374

American (AMR) AF: 0.929 AC: 37139 AN: 39976

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 22556 AN: 25398

East Asian (EAS) AF: 0.999 AC: 37518 AN: 37540

South Asian (SAS) AF: 0.934 AC: 76042 AN: 81432

European-Finnish (FIN) AF: 0.922 AC: 32596 AN: 35362

Middle Eastern (MID) AF: 0.872 AC: 3586 AN: 4112

European-Non Finnish (NFE) AF: 0.875 AC: 956011 AN: 1092458

Other (OTH) AF: 0.890 AC: 52073 AN: 58518

GnomAD4 genome AF: 0.879 AC: 133752 AN: 152242 Hom.: 58912 Cov.: 33 AF XY: 0.881 AC XY: 65607 AN XY: 74436

African (AFR) AF: 0.840 AC: 34913 AN: 41542

American (AMR) AF: 0.904 AC: 13826 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3061 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5153 AN: 5158

South Asian (SAS) AF: 0.932 AC: 4494 AN: 4824

European-Finnish (FIN) AF: 0.917 AC: 9734 AN: 10614

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.878 AC: 59723 AN: 68012

Other (OTH) AF: 0.884 AC: 1869 AN: 2114

Alfa AF: 0.879 Hom.: 61988

Bravo AF: 0.874

TwinsUK AF: 0.873 AC: 3238

ALSPAC AF: 0.875 AC: 3372

ESP6500AA AF: 0.887 AC: 2918

ESP6500EA AF: 0.900 AC: 6390

ExAC AF: 0.883 AC: 97024

Asia WGS AF: 0.971 AC: 3374 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.87
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.77
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.29
ClinPred		0.0043	T
GERP RS		-4.9
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs346803; hg19: chr17-74381567; COSMIC: COSV60059636; COSMIC: COSV60059636;