Genetic Variant RSPO4:p.Gly231Ser (chr20-960371-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001029871.4(RSPO4):c.691G>A(p.Gly231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000573 in 1,536,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.675

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048886716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO4	NM_001029871.4 link	c.691G>A	p.Gly231Ser	missense_variant	Exon 5 of 5	ENST00000217260.9	NP_001025042.2	Q2I0M5-1
RSPO4	NM_001040007.3 link	c.505G>A	p.Gly169Ser	missense_variant	Exon 4 of 4		NP_001035096.1	Q2I0M5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9 link	c.691G>A	p.Gly231Ser	missense_variant	Exon 5 of 5	1	NM_001029871.4	ENSP00000217260.4		Q2I0M5-1
RSPO4	ENST00000400634.2 link	c.505G>A	p.Gly169Ser	missense_variant	Exon 4 of 4	1		ENSP00000383475.2		Q2I0M5-2

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000634

AC:

AN:

141974

Hom.:

AF XY:

0.0000394

AC XY:

AN XY:

76164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000344

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.0000491

AC:

AN:

1384594

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

683296

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.0000284

Gnomad4 NFE exome

AF:

0.0000408

Gnomad4 OTH exome

AF:

0.0000519

GnomAD4 genome

AF:

0.000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.0000210

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691G>A (p.G231S) alteration is located in exon 5 (coding exon 5) of the RSPO4 gene. This alteration results from a G to A substitution at nucleotide position 691, causing the glycine (G) at amino acid position 231 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.6

DANN

Benign

0.61

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.081

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.90

L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.14

Sift

Benign

0.36

T;T

Sift4G

Benign

0.069

T;T

Polyphen

0.0020

B;B

Vest4

0.10

MutPred

0.24

Gain of phosphorylation at G231 (P = 9e-04);.;

MVP

0.25

MPC

0.34

ClinPred

0.044

GERP RS

-0.51

Varity_R

0.032

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over