Genetic Variant S1PR1:p.Arg13Gly (chr1-101239021-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001400.5(S1PR1):c.37C>G(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,166 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 21 hom., cov: 32)

Exomes 𝑓: 0.019 ( 320 hom. )

Consequence

S1PR1
NM_001400.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

14 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029692352).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0145 (2206/152378) while in subpopulation NFE AF = 0.0215 (1465/68040). AF 95% confidence interval is 0.0206. There are 21 homozygotes in GnomAd4. There are 1099 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2206 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001400.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
S1PR1	NM_001400.5	MANE Select	c.37C>G	p.Arg13Gly	missense	Exon 2 of 2	NP_001391.2
S1PR1	NM_001320730.2		c.37C>G	p.Arg13Gly	missense	Exon 2 of 2	NP_001307659.1	P21453
S1PR1	NR_174347.1		n.281C>G		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
S1PR1	ENST00000305352.7	TSL:1 MANE Select	c.37C>G	p.Arg13Gly	missense	Exon 2 of 2	ENSP00000305416.6	P21453
S1PR1	ENST00000475289.2	TSL:3	c.37C>G	p.Arg13Gly	missense	Exon 2 of 2	ENSP00000498038.1	P21453
S1PR1	ENST00000648480.1		c.37C>G	p.Arg13Gly	missense	Exon 2 of 2	ENSP00000497478.1	P21453

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2206

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00981

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0371

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0139

AC:

3503

AN:

251198

AF XY:

0.0138

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00537

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0358

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0186

AC:

27178

AN:

1461788

Hom.:

320

Cov.:

AF XY:

0.0182

AC XY:

13220

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

33480

American (AMR)

AF:

0.00651

AC:

291

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00586

AC:

153

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00224

AC:

193

AN:

86254

European-Finnish (FIN)

AF:

0.0367

AC:

1960

AN:

53408

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0211

AC:

23487

AN:

1111944

Other (OTH)

AF:

0.0163

AC:

983

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1575

3149

4724

6298

7873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

836

1672

2508

3344

4180

<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

AF:

0.0145

AC:

2206

AN:

152378

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1099

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00344

AC:

143

AN:

41596

American (AMR)

AF:

0.00980

AC:

150

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0371

AC:

394

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1465

AN:

68040

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0170

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0179

AC:

154

ExAC

AF:

0.0138

AC:

1680

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.040

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.75

PhyloP100

2.1

PrimateAI

Benign

0.30

PROVEAN

Benign

0.44

REVEL

Benign

0.19

Sift

Benign

0.14

Sift4G

Benign

0.40

Polyphen

0.029

Vest4

0.028

MPC

1.3

ClinPred

0.0047

GERP RS

5.0

Varity_R

0.13

gMVP

0.91

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over