rs563949840

Variant names:

• chr1-37612793-CTTG-CT
• NM_001242908.2:c.751_752delCA

Your query was ambiguous. Multiple possible variants found:

• chr1-37612794-TTGC-T
• chr1-37612794-TTGC-TTGCTGC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001242908.2(RSPO1):​c.751_752delCA​(p.Gln251ArgfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RSPO1 NM_001242908.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0518 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.751_752delCA	p.Gln251ArgfsTer32	frameshift	Exon 7 of 7	NP_001229837.1	Q2MKA7-1
	RSPO1	NM_001038633.4		c.751_752delCA	p.Gln251ArgfsTer32	frameshift	Exon 8 of 8	NP_001033722.1	Q2MKA7-1
	RSPO1	NM_001242909.2		c.670_671delCA	p.Gln224ArgfsTer32	frameshift	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.751_752delCA	p.Gln251ArgfsTer32	frameshift	Exon 7 of 7	ENSP00000348944.2	Q2MKA7-1
	RSPO1	ENST00000401068.1	TSL:1	c.751_752delCA	p.Gln251ArgfsTer32	frameshift	Exon 8 of 8	ENSP00000383846.1	Q2MKA7-1
	RSPO1	ENST00000612451.4	TSL:1	c.562_563delCA	p.Gln188ArgfsTer32	frameshift	Exon 6 of 6	ENSP00000479832.1	Q2MKA7-3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-38078465;