NM_001029871.4:c.218G>C

Variant names:

• chr20-968000-C-G
• rs74315423
• NM_001029871.4:c.218G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001029871.4(RSPO4):​c.218G>C​(p.Cys73Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C73Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001029871.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-968000-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1193.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

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.218G>C	p.Cys73Ser	missense	Exon 2 of 5	NP_001025042.2	Q2I0M5-1
	RSPO4	NM_001040007.3		c.218G>C	p.Cys73Ser	missense	Exon 2 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.218G>C	p.Cys73Ser	missense	Exon 2 of 5	ENSP00000217260.4	Q2I0M5-1
	RSPO4	ENST00000400634.2	TSL:1	c.218G>C	p.Cys73Ser	missense	Exon 2 of 4	ENSP00000383475.2	Q2I0M5-2
	RSPO4	ENST00000873320.1		c.188G>C	p.Cys63Ser	missense	Exon 2 of 5	ENSP00000543379.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249494 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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000216 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0497)
MVP		0.86
MPC		0.38
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.93
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74315423; hg19: chr20-948643;