NM_001242908.2:c.750_752dupGCA

Variant names:

• chr1-37612794-T-TTGC
• rs563949840
• NM_001242908.2:c.750_752dupGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001242908.2(RSPO1):​c.750_752dupGCA​(p.Gln251dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,612,830 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (15 hom.)
• Consequence: RSPO1 NM_001242908.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001242908.2
• BP6: Variant 1-37612794-T-TTGC is Benign according to our data. Variant chr1-37612794-T-TTGC is described in ClinVar as Benign. ClinVar VariationId is 1338212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (899/152286) while in subpopulation AFR AF = 0.021 (872/41550). AF 95% confidence interval is 0.0198. There are 7 homozygotes in GnomAd4. There are 432 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.750_752dupGCA	p.Gln251dup	disruptive_inframe_insertion	Exon 7 of 7	NP_001229837.1	Q2MKA7-1
	RSPO1	NM_001038633.4		c.750_752dupGCA	p.Gln251dup	disruptive_inframe_insertion	Exon 8 of 8	NP_001033722.1	Q2MKA7-1
	RSPO1	NM_001242909.2		c.669_671dupGCA	p.Gln224dup	disruptive_inframe_insertion	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.750_752dupGCA	p.Gln251dup	disruptive_inframe_insertion	Exon 7 of 7	ENSP00000348944.2	Q2MKA7-1
	RSPO1	ENST00000401068.1	TSL:1	c.750_752dupGCA	p.Gln251dup	disruptive_inframe_insertion	Exon 8 of 8	ENSP00000383846.1	Q2MKA7-1
	RSPO1	ENST00000612451.4	TSL:1	c.561_563dupGCA	p.Gln188dup	disruptive_inframe_insertion	Exon 6 of 6	ENSP00000479832.1	Q2MKA7-3

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 897 AN: 152168 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00136 AC: 338 AN: 248142 AF XY: 0.00107

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000583 AC: 852 AN: 1460544 Hom.: 15 Cov.: 33 AF XY: 0.000495 AC XY: 360 AN XY: 726680

African (AFR) AF: 0.0223 AC: 746 AN: 33470

American (AMR) AF: 0.000671 AC: 30 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52138

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111978

Other (OTH) AF: 0.000845 AC: 51 AN: 60374

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152286 Hom.: 7 Cov.: 33 AF XY: 0.00580 AC XY: 432 AN XY: 74484

African (AFR) AF: 0.0210 AC: 872 AN: 41550

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00634

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs563949840; hg19: chr1-38078466;