Genetic Variant ENST00000323374.8:c.95C>G (chr17-76385481-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000323374.8(SPHK1):c.95C>G(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,408,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SPHK1
ENST00000323374.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.67

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06635329).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323374.8. 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.-164C>G		5_prime_UTR	Exon 2 of 6	NP_001136073.1	Q9NYA1-1
SPHK1	NM_182965.3		c.95C>G	p.Ala32Gly	missense	Exon 2 of 6	NP_892010.2	Q9NYA1-2
SPHK1	NM_021972.4		c.-164C>G		5_prime_UTR	Exon 2 of 6	NP_068807.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPHK1	ENST00000323374.8	TSL:1	c.95C>G	p.Ala32Gly	missense	Exon 2 of 6	ENSP00000313681.3	Q9NYA1-2
SPHK1	ENST00000592299.6	TSL:1 MANE Select	c.-164C>G		5_prime_UTR	Exon 2 of 6	ENSP00000465726.2	Q9NYA1-1
SPHK1	ENST00000590959.5	TSL:1	c.-164C>G		5_prime_UTR	Exon 2 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000593

AC:

AN:

168766

AF XY:

0.0000107

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1408032

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

697360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32394

American (AMR)

AF:

0.00

AC:

AN:

40118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25396

East Asian (EAS)

AF:

0.00

AC:

AN:

37582

South Asian (SAS)

AF:

0.00

AC:

AN:

81404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1093032

Other (OTH)

AF:

0.00

AC:

AN:

58538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

(source)

DANN

Benign

0.94

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.46

M_CAP

Benign

0.022

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.0

PhyloP100

-2.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.65

REVEL

Benign

0.013

Sift

Benign

0.053

Sift4G

Benign

0.17

Polyphen

0.28

Vest4

0.12

MutPred

0.12

Gain of catalytic residue at A32 (P = 0.0715)

MVP

0.085

MPC

0.38

ClinPred

0.051

GERP RS

-2.6

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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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