Genetic Variant NM_001142601.2:c.149C>T (chr17-76386123-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001142601.2(SPHK1):c.149C>T(p.Thr50Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000021 ( 0 hom. )

Consequence

SPHK1
NM_001142601.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.43

Publications

0 publications found

Variant links:

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]

SPHK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19292349).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPHK1	NM_001142601.2	MANE Select	c.149C>T	p.Thr50Met	missense	Exon 3 of 6	NP_001136073.1	Q9NYA1-1
SPHK1	NM_182965.3		c.407C>T	p.Thr136Met	missense	Exon 3 of 6	NP_892010.2	Q9NYA1-2
SPHK1	NM_021972.4		c.191C>T	p.Thr64Met	missense	Exon 3 of 6	NP_068807.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPHK1	ENST00000592299.6	TSL:1 MANE Select	c.149C>T	p.Thr50Met	missense	Exon 3 of 6	ENSP00000465726.2	Q9NYA1-1
SPHK1	ENST00000323374.8	TSL:1	c.407C>T	p.Thr136Met	missense	Exon 3 of 6	ENSP00000313681.3	Q9NYA1-2
SPHK1	ENST00000590959.5	TSL:1	c.191C>T	p.Thr64Met	missense	Exon 3 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000822

AC:

AN:

243292

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1443944

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33168

American (AMR)

AF:

0.00

AC:

AN:

44226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39280

South Asian (SAS)

AF:

0.00

AC:

AN:

85918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102486

Other (OTH)

AF:

0.00

AC:

AN:

59690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.75

M_CAP

Benign

0.043

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.5

PhyloP100

-1.4

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.10

Sift

Benign

0.052

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.37

MutPred

0.41

Gain of MoRF binding (P = 0.2133)

MVP

0.21

MPC

0.84

ClinPred

0.93

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

Mutation Taster

=64/36

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over