rs387907027

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001029871.4(RSPO4):c.190C>T(p.Arg64Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.71

Publications

5 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, Labcorp Genetics (formerly Invitae), Orphanet

RSPO4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 20-968028-G-A is Pathogenic according to our data. Variant chr20-968028-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30846.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO4	NM_001029871.4	MANE Select	c.190C>T	p.Arg64Cys	missense	Exon 2 of 5	NP_001025042.2
	RSPO4	NM_001040007.3		c.190C>T	p.Arg64Cys	missense	Exon 2 of 4	NP_001035096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO4	ENST00000217260.9	TSL:1 MANE Select	c.190C>T	p.Arg64Cys	missense	Exon 2 of 5	ENSP00000217260.4
	RSPO4	ENST00000400634.2	TSL:1	c.190C>T	p.Arg64Cys	missense	Exon 2 of 4	ENSP00000383475.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249418

AF XY:

0.0000222

show subpopulations

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:

0.0000353

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111992

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68048

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000321

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000331

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anonychia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.1

PhyloP100

4.7

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.86

MPC

0.39

ClinPred

0.90

GERP RS

5.1

Varity_R

0.57

gMVP

0.69

Mutation Taster

=24/76

disease causing (ClinVar)

(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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over