1-37612891-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001242908.2(RSPO1):c.656G>A(p.Arg219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

RSPO1
NM_001242908.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.783

Variant links:

Genes affected

RSPO1 (HGNC:21679): (R-spondin 1) This gene encodes a secreted activator protein with two cysteine-rich, furin-like domains and one thrombospondin type 1 domain. The encoded protein is a ligand for leucine-rich repeat-containing G-protein coupled receptors (LGR proteins) and positively regulates the Wnt signaling pathway. In mice, the protein induces the rapid onset of crypt cell proliferation and increases intestinal epithelial healing, providing a protective effect against chemotherapy-induced adverse effects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

RSPO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14397383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO1	NM_001242908.2 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 7 of 7	ENST00000356545.7	NP_001229837.1	Q2MKA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPO1	ENST00000356545.7 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 7 of 7	1	NM_001242908.2	ENSP00000348944.2	Q2MKA7-1
RSPO1	ENST00000401068.1 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 8 of 8	1		ENSP00000383846.1	Q2MKA7-1
RSPO1	ENST00000612451.4 link	c.467G>A	p.Arg156Gln	missense_variant	Exon 6 of 6	1		ENSP00000479832.1	Q2MKA7-3
RSPO1	ENST00000615459.4 link	c.575G>A	p.Arg192Gln	missense_variant	Exon 7 of 7	2		ENSP00000481178.1	Q2MKA7-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249434

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the RSPO1 protein (p.Arg219Gln). This variant is present in population databases (rs372057847, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RSPO1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;.;T;T

Eigen

Benign

-0.040

Eigen_PC

Benign

0.063

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

T;T;.;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.0

.;.;M;M

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

.;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.072

.;.;T;T

Sift4G

Benign

0.082

T;T;T;T

Polyphen

0.95

P;.;P;P

Vest4

0.16

MutPred

0.17

.;.;Loss of methylation at R219 (P = 0.0249);Loss of methylation at R219 (P = 0.0249);

MVP

0.73

MPC

0.31

ClinPred

0.084

GERP RS

4.1

Varity_R

0.085

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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