1-37612821-G-A

Variant names:

• chr1-37612821-G-A
• rs200509081
• NM_001242908.2:c.726C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001242908.2(RSPO1):​c.726C>T​(p.Arg242Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RSPO1 NM_001242908.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=2.26 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242908.2. 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
	RSPO1	NM_001242908.2	MANE Select	c.726C>T	p.Arg242Arg	synonymous	Exon 7 of 7	NP_001229837.1	Q2MKA7-1
	RSPO1	NM_001038633.4		c.726C>T	p.Arg242Arg	synonymous	Exon 8 of 8	NP_001033722.1	Q2MKA7-1
	RSPO1	NM_001242909.2		c.645C>T	p.Arg215Arg	synonymous	Exon 7 of 7	NP_001229838.1	Q2MKA7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO1	ENST00000356545.7	TSL:1 MANE Select	c.726C>T	p.Arg242Arg	synonymous	Exon 7 of 7	ENSP00000348944.2	Q2MKA7-1
	RSPO1	ENST00000401068.1	TSL:1	c.726C>T	p.Arg242Arg	synonymous	Exon 8 of 8	ENSP00000383846.1	Q2MKA7-1
	RSPO1	ENST00000612451.4	TSL:1	c.537C>T	p.Arg179Arg	synonymous	Exon 6 of 6	ENSP00000479832.1	Q2MKA7-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200509081; hg19: chr1-38078493;