rs387907028

chr20-968019-C-Gchr20-968019-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001029871.4(RSPO4):c.199G>C(p.Gly67Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 19) in uniprot entity RSPO4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001029871.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 20-968019-C-G is Pathogenic according to our data. Variant chr20-968019-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 30847.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO4	NM_001029871.4	c.199G>C	p.Gly67Arg	missense_variant	2/5	ENST00000217260.9
RSPO4	NM_001040007.3	c.199G>C	p.Gly67Arg	missense_variant	2/4
RSPO4	XM_017027839.2	c.199G>C	p.Gly67Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO4	ENST00000217260.9	c.199G>C	p.Gly67Arg	missense_variant	2/5	1	NM_001029871.4	P1
RSPO4	ENST00000400634.2	c.199G>C	p.Gly67Arg	missense_variant	2/4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Anonychia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.91		Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);
MVP		0.90
MPC		0.38
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.74
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907028; hg19: chr20-948662;