9-89001787-A-T

Variant names:

• chr9-89001787-A-T
• rs909885163
• NM_005226.4:c.587A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005226.4(S1PR3):​c.587A>T​(p.Tyr196Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: S1PR3 NM_005226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

Genes affected

S1PR3 (HGNC:3167): (sphingosine-1-phosphate receptor 3) This gene encodes a member of the EDG family of receptors, which are G protein-coupled receptors. This protein has been identified as a functional receptor for sphingosine 1-phosphate and likely contributes to the regulation of angiogenesis and vascular endothelial cell function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR3	NM_005226.4	c.587A>T	p.Tyr196Phe	missense_variant	Exon 2 of 2	ENST00000358157.3	NP_005217.2
S1PR3	NM_001395848.1	c.587A>T	p.Tyr196Phe	missense_variant	Exon 3 of 3		NP_001382777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S1PR3	ENST00000358157.3	c.587A>T	p.Tyr196Phe	missense_variant	Exon 2 of 2	1	NM_005226.4	ENSP00000350878.2
S1PR3	ENST00000375846.3	c.587A>T	p.Tyr196Phe	missense_variant	Exon 1 of 1	6		ENSP00000365006.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.587A>T (p.Y196F) alteration is located in exon 2 (coding exon 1) of the S1PR3 gene. This alteration results from a A to T substitution at nucleotide position 587, causing the tyrosine (Y) at amino acid position 196 to be replaced by a phenylalanine (F). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	D;D
Vest4		0.40
MutPred		0.81		Gain of methylation at K195 (P = 0.0256);Gain of methylation at K195 (P = 0.0256);
MVP		0.79
MPC		1.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.45
gMVP		0.76

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: rs909885163; hg19: chr9-91616702;