9-89001223-G-A

Variant names:

• chr9-89001223-G-A
• rs150141136
• NM_005226.4:c.23G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005226.4(S1PR3):​c.23G>A​(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,612,818 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: S1PR3 NM_005226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.89

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041374266).
• BS2: High Homozygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S1PR3	NM_005226.4	c.23G>A	p.Arg8His	missense_variant	Exon 2 of 2	ENST00000358157.3	NP_005217.2
S1PR3	NM_001395848.1	c.23G>A	p.Arg8His	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.23G>A	p.Arg8His	missense_variant	Exon 2 of 2	1	NM_005226.4	ENSP00000350878.2
S1PR3	ENST00000375846.3	c.23G>A	p.Arg8His	missense_variant	Exon 1 of 1	6		ENSP00000365006.3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00121 AC: 303 AN: 250686 Hom.: 0 AF XY: 0.00111 AC XY: 150 AN XY: 135724

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00222 AC: 3240 AN: 1460580 Hom.: 7 Cov.: 30 AF XY: 0.00215 AC XY: 1559 AN XY: 726312

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74446

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00121 AC: 147

EpiCase AF: 0.00191

EpiControl AF: 0.00196

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23G>A (p.R8H) alteration is located in exon 2 (coding exon 1) of the S1PR3 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a histidine (H). 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	Benign	0.081
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.026
DANN	Benign	0.87
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.055
Sift	Benign	0.14	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;B
Vest4		0.084
MVP		0.20
MPC		0.56
ClinPred		0.0048	T
GERP RS		-9.4
Varity_R		0.019
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150141136; hg19: chr9-91616138;