17-76386899-C-T

Variant names:

• chr17-76386899-C-T
• rs9901836
• NM_001142601.2:c.468C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001142601.2(SPHK1):​c.468C>T​(p.His156His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,611,982 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: SPHK1 NM_001142601.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0190
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-76386899-C-T is Benign according to our data. Variant chr17-76386899-C-T is described in ClinVar as Benign. ClinVar VariationId is 785584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BS2: High AC in GnomAd4 at 322 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHK1	NM_001142601.2	MANE Select	c.468C>T	p.His156His	synonymous	Exon 6 of 6	NP_001136073.1	Q9NYA1-1
	SPHK1	NM_182965.3		c.726C>T	p.His242His	synonymous	Exon 6 of 6	NP_892010.2	Q9NYA1-2
	SPHK1	NM_021972.4		c.510C>T	p.His170His	synonymous	Exon 6 of 6	NP_068807.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHK1	ENST00000592299.6	TSL:1 MANE Select	c.468C>T	p.His156His	synonymous	Exon 6 of 6	ENSP00000465726.2	Q9NYA1-1
	SPHK1	ENST00000323374.8	TSL:1	c.726C>T	p.His242His	synonymous	Exon 6 of 6	ENSP00000313681.3	Q9NYA1-2
	SPHK1	ENST00000590959.5	TSL:1	c.510C>T	p.His170His	synonymous	Exon 6 of 6	ENSP00000468547.1	Q9NYA1-3

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000559 AC: 140 AN: 250418 AF XY: 0.000436

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1459620 Hom.: 1 Cov.: 31 AF XY: 0.000194 AC XY: 141 AN XY: 725790

African (AFR) AF: 0.00804 AC: 269 AN: 33470

American (AMR) AF: 0.000404 AC: 18 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86090

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52816

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110852

Other (OTH) AF: 0.000348 AC: 21 AN: 60302

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74508

African (AFR) AF: 0.00757 AC: 315 AN: 41588

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.00240

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		0.019

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: rs9901836; hg19: chr17-74382980;