rs3835397

Positions:

• chr1-101236991-AG-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_001320730.2(S1PR1):​c.-164+1delG variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 152,120 control chromosomes in the GnomAD database, including 1,148 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.090 (1148 hom., cov: 29)
  • Exomes 𝑓: 0.041 (0 hom.)
• Consequence: S1PR1 NM_001320730.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.246

Genes affected

S1PR1 (HGNC:3165): (sphingosine-1-phosphate receptor 1) The protein encoded by this gene is structurally similar to G protein-coupled receptors and is highly expressed in endothelial cells. It binds the ligand sphingosine-1-phosphate with high affinity and high specificity, and suggested to be involved in the processes that regulate the differentiation of endothelial cells. Activation of this receptor induces cell-cell adhesion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

S1PR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.080069624 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
S1PR1	NM_001400.5	c.-271delG		upstream_gene_variant		ENST00000305352.7	NP_001391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
S1PR1	ENST00000475821.2	c.-164+1delG		splice_donor_variant, intron_variant		2		ENSP00000498194.1
S1PR1	ENST00000561748.2	n.94delG		non_coding_transcript_exon_variant	1/3	6
S1PR1	ENST00000305352.7	c.-271delG		upstream_gene_variant		1	NM_001400.5	ENSP00000305416.6

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13614 AN: 151852 Hom.: 1147 Cov.: 29

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.0574

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0364

Gnomad OTH AF: 0.0882

GnomAD4 exome AF: 0.0405 AC: 6 AN: 148 Hom.: 0 Cov.: 0 AF XY: 0.0500 AC XY: 5 AN XY: 100

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.0513

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0896 AC: 13621 AN: 151972 Hom.: 1148 Cov.: 29 AF XY: 0.0879 AC XY: 6530 AN XY: 74304

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.0552

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.0573

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.0364

Gnomad4 OTH AF: 0.0868

Alfa AF: 0.0115 Hom.: 2

Bravo AF: 0.0971

Asia WGS AF: 0.0870 AC: 304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs3835397; hg19: chr1-101702547;