1-37627051-C-T

Variant names:

• chr1-37627051-C-T
• rs4074961
• NM_001242908.2:c.94+2517G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001242908.2(RSPO1):​c.94+2517G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 151,998 control chromosomes in the GnomAD database, including 12,683 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (12683 hom., cov: 30)
• Consequence: RSPO1 NM_001242908.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.460
• Publications: 24 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

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.94+2517G>A		intron	N/A	NP_001229837.1	Q2MKA7-1
	RSPO1	NM_001038633.4		c.94+2517G>A		intron	N/A	NP_001033722.1	Q2MKA7-1
	RSPO1	NM_001242909.2		c.13+2838G>A		intron	N/A	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.94+2517G>A		intron	N/A	ENSP00000348944.2	Q2MKA7-1
	RSPO1	ENST00000401068.1	TSL:1	c.94+2517G>A		intron	N/A	ENSP00000383846.1	Q2MKA7-1
	RSPO1	ENST00000612451.4	TSL:1	c.94+2517G>A		intron	N/A	ENSP00000479832.1	Q2MKA7-3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59653 AN: 151880 Hom.: 12666 Cov.: 30

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.393 AC: 59703 AN: 151998 Hom.: 12683 Cov.: 30 AF XY: 0.397 AC XY: 29500 AN XY: 74264

African (AFR) AF: 0.226 AC: 9351 AN: 41446

American (AMR) AF: 0.502 AC: 7677 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1344 AN: 3466

East Asian (EAS) AF: 0.510 AC: 2626 AN: 5154

South Asian (SAS) AF: 0.413 AC: 1987 AN: 4808

European-Finnish (FIN) AF: 0.515 AC: 5445 AN: 10568

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29825 AN: 67958

Other (OTH) AF: 0.423 AC: 893 AN: 2112

Alfa AF: 0.425 Hom.: 61202

Bravo AF: 0.383

Asia WGS AF: 0.488 AC: 1696 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.0
DANN	Benign	0.89
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4074961; hg19: chr1-38092723; COSMIC: COSV62974990;