19-3178847-G-T

Variant names:

• chr19-3178847-G-T
• rs575226710
• NM_003775.4:c.55G>T

Variant summary

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

The NM_003775.4(S1PR4):​c.55G>T​(p.Gly19Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,534,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G19S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: S1PR4 NM_003775.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 0 publications found

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]

ENSG00000289471 (HGNC:):

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=0.16644752).

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.55G>T	p.Gly19Cys	missense	Exon 1 of 1	NP_003766.1	O95977

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S1PR4	ENST00000246115.5	TSL:6 MANE Select	c.55G>T	p.Gly19Cys	missense	Exon 1 of 1	ENSP00000246115.3	O95977
	S1PR4	ENST00000591346.1	TSL:3	n.100-367G>T		intron	N/A
	ENSG00000289471	ENST00000687895.2		n.-139C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382598 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 683384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30076

American (AMR) AF: 0.00 AC: 0 AN: 35086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24698

East Asian (EAS) AF: 0.00 AC: 0 AN: 34694

South Asian (SAS) AF: 0.00 AC: 0 AN: 79104

European-Finnish (FIN) AF: 0.0000262 AC: 1 AN: 38192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079102

Other (OTH) AF: 0.00 AC: 0 AN: 57450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.62
DANN	Benign	0.94
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-1.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.22
MutPred		0.40		Loss of disorder (P = 0.0524)
MVP		0.47
MPC		0.74
ClinPred		0.56	D
GERP RS		-7.1
PromoterAI		0.029	Neutral
Varity_R		0.12
gMVP		0.53
Mutation Taster		=96/4	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

dbSNP: rs575226710; hg19: chr19-3178845;