Variant chr1-37612875-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001242908.2(RSPO1):c.672C>A(p.Asn224Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,304 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 0.0000066 ( 0 hom., cov: 33)

Consequence

RSPO1
NM_001242908.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.677

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:

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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=0.12757495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPO1	NM_001242908.2 linkuse as main transcript	c.672C>A	p.Asn224Lys	missense_variant	7/7	ENST00000356545.7	NP_001229837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPO1	ENST00000356545.7 linkuse as main transcript	c.672C>A	p.Asn224Lys	missense_variant	7/7	1	NM_001242908.2	ENSP00000348944	P1	Q2MKA7-1
RSPO1	ENST00000401068.1 linkuse as main transcript	c.672C>A	p.Asn224Lys	missense_variant	8/8	1		ENSP00000383846	P1	Q2MKA7-1
RSPO1	ENST00000612451.4 linkuse as main transcript	c.483C>A	p.Asn161Lys	missense_variant	6/6	1		ENSP00000479832		Q2MKA7-3
RSPO1	ENST00000615459.4 linkuse as main transcript	c.591C>A	p.Asn197Lys	missense_variant	7/7	2		ENSP00000481178		Q2MKA7-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.672C>A (p.N224K) alteration is located in exon 8 (coding exon 5) of the RSPO1 gene. This alteration results from a C to A substitution at nucleotide position 672, causing the asparagine (N) at amino acid position 224 to be replaced by a lysine (K). 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

Benign

0.10

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

.;.;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.62

T;T;.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.97

.;.;L;L

MutationTaster

Benign

0.87

D;D;D;D;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.85

.;.;N;N

REVEL

Benign

0.080

Sift

Benign

0.52

.;.;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0060

B;.;B;B

Vest4

0.19

MutPred

0.22

.;.;Gain of ubiquitination at N224 (P = 0.0592);Gain of ubiquitination at N224 (P = 0.0592);

MVP

0.72

MPC

0.31

ClinPred

0.11

GERP RS

2.6

Varity_R

0.096

gMVP

0.46

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over