Genetic Variant NM_005226.4:c.-148+196C>T (chr9-88991891-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005226.4(S1PR3):c.-148+196C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,196 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

S1PR3
NM_005226.4 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.60

Variant links:

Genes affected

S1PR3 (HGNC:3167): (sphingosine-1-phosphate receptor 3) This gene encodes a member of the EDG family of receptors, which are G protein-coupled receptors. This protein has been identified as a functional receptor for sphingosine 1-phosphate and likely contributes to the regulation of angiogenesis and vascular endothelial cell function. [provided by RefSeq, Jul 2008]

S1PR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0133262575).

BS2

High Homozygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
S1PR3	NM_005226.4 link	c.-148+196C>T	intron_variant	Intron 1 of 1	ENST00000358157.3	NP_005217.2	Q99500
S1PR3	NM_001395848.1 link	c.-148+196C>T	intron_variant	Intron 2 of 2		NP_001382777.1
S1PR3	NR_172882.1 link	n.588C>T	non_coding_transcript_exon_variant	Exon 3 of 3
S1PR3	NR_172883.1 link	n.645C>T	non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
S1PR3	ENST00000358157.3 link	c.-148+196C>T	intron_variant	Intron 1 of 1	1	NM_005226.4	ENSP00000350878.2	Q99500
S1PR3	ENST00000334490.5 link	n.580C>T	non_coding_transcript_exon_variant	Exon 3 of 3	1
S1PR3	ENST00000375850.3 link	n.686C>T	non_coding_transcript_exon_variant	Exon 2 of 2	3
S1PR3	ENST00000648341.1 link	n.588C>T	non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000728

AC:

183

AN:

251422

Hom.:

AF XY:

0.000751

AC XY:

102

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00105

AC:

1542

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

749

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152314

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.000631

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512C>T (p.T171I) alteration is located in exon 3 (coding exon 3) of the C9orf47 gene. This alteration results from a C to T substitution at nucleotide position 512, causing the threonine (T) at amino acid position 171 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.080

DANN

Benign

0.91

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.33

T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.0

REVEL

Benign

0.16

MVP

0.040

ClinPred

0.036

GERP RS

-5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over