Genetic Variant S1PR4:p.Arg50Gln (chr19-3178941-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003775.4(S1PR4):c.149G>A(p.Arg50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,536,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

S1PR4
NM_003775.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.175

Publications

0 publications found

Variant links:

Genes affected

S1PR4 (HGNC:3170): (sphingosine-1-phosphate receptor 4) This gene is a member of the endothelial differentiation, G-protein-coupled (EDG)) receptor gene family. EDG receptors bind lysophospholipids or lysosphingolipids as ligands, and are involved in cell signalling in many different cell types. This EDG receptor gene is intronless and is specifically expressed in the lymphoid tissue. [provided by RefSeq, Jul 2008]

S1PR4 links:

ENSG00000289471 (HGNC:):

ENSG00000289471 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018398583).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003775.4. 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
	S1PR4	NM_003775.4	MANE Select	c.149G>A	p.Arg50Gln	missense	Exon 1 of 1	NP_003766.1	O95977

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
S1PR4	ENST00000246115.5	TSL:6 MANE Select	c.149G>A	p.Arg50Gln	missense	Exon 1 of 1	ENSP00000246115.3	O95977
S1PR4	ENST00000591346.1	TSL:3	n.100-273G>A		intron	N/A
ENSG00000289471	ENST00000687895.2		n.-233C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000125

AC:

AN:

135722

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000913

Gnomad FIN exome

AF:

0.000146

Gnomad NFE exome

AF:

0.0000755

Gnomad OTH exome

AF:

0.000251

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1384820

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

683950

show subpopulations

African (AFR)

AF:

0.0000318

AC:

AN:

31412

American (AMR)

AF:

0.000225

AC:

AN:

35600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35906

South Asian (SAS)

AF:

0.000138

AC:

AN:

79556

European-Finnish (FIN)

AF:

0.0000275

AC:

AN:

36390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4202

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1079676

Other (OTH)

AF:

0.0000174

AC:

AN:

57604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000689

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000367

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.045

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.5

PhyloP100

0.17

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.0

REVEL

Benign

0.20

Sift

Benign

0.31

Sift4G

Benign

0.62

Polyphen

0.79

Vest4

0.12

MutPred

0.59

Loss of methylation at R50 (P = 0.027)

MVP

0.70

MPC

0.72

ClinPred

0.059

GERP RS

2.6

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.076

gMVP

0.41

Mutation Taster

=94/6

polymorphism

(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