chr1-37613865-G-A

Position:

chr1-37613865-G-A

Variant summary

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

The NM_001242908.2(RSPO1):c.464C>T(p.Pro155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

RSPO1
NM_001242908.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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=0.086111635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO1	NM_001242908.2 linkuse as main transcript	c.464C>T	p.Pro155Leu	missense_variant	6/7	ENST00000356545.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO1	ENST00000356545.7 linkuse as main transcript	c.464C>T	p.Pro155Leu	missense_variant	6/7	1	NM_001242908.2	P1	Q2MKA7-1
RSPO1	ENST00000401068.1 linkuse as main transcript	c.464C>T	p.Pro155Leu	missense_variant	7/8	1		P1	Q2MKA7-1
RSPO1	ENST00000612451.4 linkuse as main transcript	c.436+319C>T		intron_variant		1			Q2MKA7-3
RSPO1	ENST00000615459.4 linkuse as main transcript	c.383C>T	p.Pro128Leu	missense_variant	6/7	2			Q2MKA7-2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000253

AC:

AN:

249322

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000380

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000200

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000230

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000319

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000604

AC:

ExAC

AF:

0.000339

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 155 of the RSPO1 protein (p.Pro155Leu). This variant is present in population databases (rs201102260, gnomAD 0.04%). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine 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

0.063

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.44

.;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.85

T;.;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.5

.;N;N

REVEL

Benign

0.038

Sift

Benign

0.18

.;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.24

MVP

0.44

MPC

0.28

ClinPred

0.019

GERP RS

1.4

Varity_R

0.042

gMVP

0.27

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