Genetic Variant NM_001029871.4:c.547G>T (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:

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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

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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