chr17-76387020-T-C

Position:

• chr17-76387020-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142601.2(SPHK1):​c.589T>C​(p.Phe197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000082 (0 hom.)
• Consequence: SPHK1 NM_001142601.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.218

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031464696).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPHK1	NM_001142601.2	c.589T>C	p.Phe197Leu	missense_variant	6/6	ENST00000592299.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPHK1	ENST00000592299.6	c.589T>C	p.Phe197Leu	missense_variant	6/6	1	NM_001142601.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461362 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.847T>C (p.F283L) alteration is located in exon 6 (coding exon 6) of the SPHK1 gene. This alteration results from a T to C substitution at nucleotide position 847, causing the phenylalanine (F) at amino acid position 283 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.6
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T;T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.33	N;N;.;.;N
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.14	N;.;.;N;N
REVEL	Benign	0.024
Sift	Benign	1.0	T;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B
Vest4		0.048
MutPred		0.39		Loss of methylation at R199 (P = 0.1033);Loss of methylation at R199 (P = 0.1033);.;.;Loss of methylation at R199 (P = 0.1033);
MVP		0.15
MPC		0.35
ClinPred		0.097	T
GERP RS		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-74383101;