dbSNP rs778288742: RSPO4:p.Val183Leu (chr20-963983-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001029871.4(RSPO4):c.547G>T(p.Val183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

0 publications found

Variant links:

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)

RSPO4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16307464).

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.547G>T	p.Val183Leu	missense	Exon 4 of 5	NP_001025042.2	Q2I0M5-1
	RSPO4	NM_001040007.3		c.409+3191G>T		intron	N/A	NP_001035096.1	Q2I0M5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPO4	ENST00000217260.9	TSL:1 MANE Select	c.547G>T	p.Val183Leu	missense	Exon 4 of 5	ENSP00000217260.4	Q2I0M5-1
RSPO4	ENST00000400634.2	TSL:1	c.409+3191G>T		intron	N/A	ENSP00000383475.2	Q2I0M5-2
RSPO4	ENST00000873320.1		c.517G>T	p.Val173Leu	missense	Exon 4 of 5	ENSP00000543379.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.0

PhyloP100

1.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.2

REVEL

Benign

0.11

Sift

Benign

0.13

Sift4G

Benign

0.25

Polyphen

0.34

Vest4

0.36

MutPred

0.24

Loss of catalytic residue at V183 (P = 0.074)

MVP

0.46

MPC

0.053

ClinPred

0.18

GERP RS

4.1

Varity_R

0.065

gMVP

0.15

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over