NM_001400.5:c.458A>G

Variant names:

• chr1-101239442-A-G
• NM_001400.5:c.458A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001400.5(S1PR1):​c.458A>G​(p.Asn153Ser) 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 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: S1PR1 NM_001400.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2391234).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S1PR1	NM_001400.5	MANE Select	c.458A>G	p.Asn153Ser	missense	Exon 2 of 2	NP_001391.2
	S1PR1	NM_001320730.2		c.458A>G	p.Asn153Ser	missense	Exon 2 of 2	NP_001307659.1	P21453
	S1PR1	NR_174347.1		n.702A>G		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S1PR1	ENST00000305352.7	TSL:1 MANE Select	c.458A>G	p.Asn153Ser	missense	Exon 2 of 2	ENSP00000305416.6	P21453
	S1PR1	ENST00000475289.2	TSL:3	c.458A>G	p.Asn153Ser	missense	Exon 2 of 2	ENSP00000498038.1	P21453
	S1PR1	ENST00000648480.1		c.458A>G	p.Asn153Ser	missense	Exon 2 of 2	ENSP00000497478.1	P21453

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N
PhyloP100		6.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.075
Sift	Benign	0.17	T
Sift4G	Benign	0.67	T
Polyphen		0.0070	B
Vest4		0.42
MutPred		0.41		Loss of catalytic residue at N153 (P = 0.0081)
MVP		0.28
MPC		0.86
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.10
gMVP		0.63
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

hg19: chr1-101704998;