20-960381-C-A

Variant names:

• chr20-960381-C-A
• rs369860447
• NM_001029871.4:c.681G>T

Variant summary

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

The NM_001029871.4(RSPO4):​c.681G>T​(p.Pro227Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.880
• Publications: 0 publications found

Genes affected

RSPO4 (HGNC:16175): (R-spondin 4) This gene encodes a member of the R-spondin family of proteins that share a common domain organization consisting of a signal peptide, cysteine-rich/furin-like domain, thrombospondin domain and a C-terminal basic region. The encoded protein may be involved in activation of Wnt/beta-catenin signaling pathways. Mutations in this gene are associated with anonychia congenital. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

RSPO4 Gene-Disease associations (from GenCC):

• nonsyndromic congenital nail disorder 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

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=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.88 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029871.4. 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
	RSPO4	NM_001029871.4	MANE Select	c.681G>T	p.Pro227Pro	synonymous	Exon 5 of 5	NP_001025042.2	Q2I0M5-1
	RSPO4	NM_001040007.3		c.495G>T	p.Pro165Pro	synonymous	Exon 4 of 4	NP_001035096.1	Q2I0M5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO4	ENST00000217260.9	TSL:1 MANE Select	c.681G>T	p.Pro227Pro	synonymous	Exon 5 of 5	ENSP00000217260.4	Q2I0M5-1
	RSPO4	ENST00000400634.2	TSL:1	c.495G>T	p.Pro165Pro	synonymous	Exon 4 of 4	ENSP00000383475.2	Q2I0M5-2
	RSPO4	ENST00000873320.1		c.651G>T	p.Pro217Pro	synonymous	Exon 5 of 5	ENSP00000543379.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000699 AC: 1 AN: 143024 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385368 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683708

African (AFR) AF: 0.00 AC: 0 AN: 31610

American (AMR) AF: 0.00 AC: 0 AN: 35842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35780

South Asian (SAS) AF: 0.00 AC: 0 AN: 79242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079088

Other (OTH) AF: 0.0000173 AC: 1 AN: 57884

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.29
DANN	Benign	0.67
PhyloP100		-0.88

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: rs369860447; hg19: chr20-941024;