1-101239016-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001400.5(S1PR1):c.32C>A(p.Ala11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,613,730 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (45 hom.)
• Consequence: S1PR1 NM_001400.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.97

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022358298).
• BP6: Variant 1-101239016-C-A is Benign according to our data. Variant chr1-101239016-C-A is described in ClinVar as [Benign]. Clinvar id is 784445.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2079/152382) while in subpopulation AFR AF= 0.0479 (1991/41588). AF 95% confidence interval is 0.0461. There are 48 homozygotes in gnomad4. There are 1004 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2077 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
S1PR1	NM_001400.5	c.32C>A	p.Ala11Asp	missense_variant	2/2	ENST00000305352.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
S1PR1	ENST00000305352.7	c.32C>A	p.Ala11Asp	missense_variant	2/2	1	NM_001400.5	P1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2077 AN: 152264 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00378 AC: 947 AN: 250580 Hom.: 15 AF XY: 0.00286 AC XY: 388 AN XY: 135470

Gnomad AFR exome AF: 0.0521

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00135 AC: 1969 AN: 1461348 Hom.: 45 Cov.: 32 AF XY: 0.00114 AC XY: 832 AN XY: 726934

Gnomad4 AFR exome AF: 0.0484

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.0136 AC: 2079 AN: 152382 Hom.: 48 Cov.: 32 AF XY: 0.0135 AC XY: 1004 AN XY: 74524

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00344 Hom.: 8

Bravo AF: 0.0150

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00446 AC: 541

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.93
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.51	T;.;.;.;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.68	N
PrimateAI	Benign	0.45	T
Polyphen		0.0050	.;B;B;B;B
Vest4		0.11
MVP		0.64
MPC		1.5
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.091
gMVP		0.94

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: rs61734752; hg19: chr1-101704572;