NM_001242908.2:c.626-37T>A

Variant names:

• chr1-37612958-A-T
• rs55852308
• NM_001242908.2:c.626-37T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001242908.2(RSPO1):​c.626-37T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,611,032 control chromosomes in the GnomAD database, including 52,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3843 hom., cov: 33)
  • Exomes 𝑓: 0.26 (48748 hom.)
• Consequence: RSPO1 NM_001242908.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-37612958-A-T is Benign according to our data. Variant chr1-37612958-A-T is described in ClinVar as Benign. ClinVar VariationId is 1229324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 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.626-37T>A		intron	N/A	NP_001229837.1	Q2MKA7-1
	RSPO1	NM_001038633.4		c.626-37T>A		intron	N/A	NP_001033722.1	Q2MKA7-1
	RSPO1	NM_001242909.2		c.545-37T>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.626-37T>A		intron	N/A	ENSP00000348944.2	Q2MKA7-1
	RSPO1	ENST00000401068.1	TSL:1	c.626-37T>A		intron	N/A	ENSP00000383846.1	Q2MKA7-1
	RSPO1	ENST00000612451.4	TSL:1	c.437-37T>A		intron	N/A	ENSP00000479832.1	Q2MKA7-3

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31972 AN: 152080 Hom.: 3845 Cov.: 33

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.246 AC: 60690 AN: 246774 AF XY: 0.247

Gnomad AFR exome AF: 0.0892

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.256 AC: 373190 AN: 1458834 Hom.: 48748 Cov.: 33 AF XY: 0.256 AC XY: 185911 AN XY: 725860

African (AFR) AF: 0.0846 AC: 2831 AN: 33448

American (AMR) AF: 0.242 AC: 10806 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8650 AN: 26124

East Asian (EAS) AF: 0.272 AC: 10779 AN: 39692

South Asian (SAS) AF: 0.242 AC: 20852 AN: 86200

European-Finnish (FIN) AF: 0.195 AC: 10156 AN: 52216

Middle Eastern (MID) AF: 0.320 AC: 1733 AN: 5422

European-Non Finnish (NFE) AF: 0.263 AC: 291891 AN: 1110746

Other (OTH) AF: 0.257 AC: 15492 AN: 60290

GnomAD4 genome AF: 0.210 AC: 31952 AN: 152198 Hom.: 3843 Cov.: 33 AF XY: 0.209 AC XY: 15526 AN XY: 74418

African (AFR) AF: 0.0946 AC: 3931 AN: 41534

American (AMR) AF: 0.250 AC: 3828 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1142 AN: 3466

East Asian (EAS) AF: 0.288 AC: 1484 AN: 5158

South Asian (SAS) AF: 0.229 AC: 1103 AN: 4824

European-Finnish (FIN) AF: 0.193 AC: 2046 AN: 10594

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17734 AN: 67998

Other (OTH) AF: 0.233 AC: 492 AN: 2114

Alfa AF: 0.247 Hom.: 930

Bravo AF: 0.212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.73
PhyloP100		-1.2
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: rs55852308; hg19: chr1-38078630; COSMIC: COSV62974389;