Variant 20-960428-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001029871.4(RSPO4):c.634C>T(p.Arg212Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,539,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14205766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPO4	NM_001029871.4 linkuse as main transcript	c.634C>T	p.Arg212Cys	missense_variant	5/5	ENST00000217260.9	NP_001025042.2
RSPO4	NM_001040007.3 linkuse as main transcript	c.448C>T	p.Arg150Cys	missense_variant	4/4		NP_001035096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9 linkuse as main transcript	c.634C>T	p.Arg212Cys	missense_variant	5/5	1	NM_001029871.4	ENSP00000217260	P1	Q2I0M5-1
RSPO4	ENST00000400634.2 linkuse as main transcript	c.448C>T	p.Arg150Cys	missense_variant	4/4	1		ENSP00000383475		Q2I0M5-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000552

AC:

AN:

144838

Hom.:

AF XY:

0.0000774

AC XY:

AN XY:

77478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000548

Gnomad SAS exome

AF:

0.0000438

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000389

AC:

AN:

1387458

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

684820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000279

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000296

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000139

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000208

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.634C>T (p.R212C) alteration is located in exon 5 (coding exon 5) of the RSPO4 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the arginine (R) at amino acid position 212 to be replaced by a cysteine (C). 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

Uncertain

0.47

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.88

D;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

-0.099

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

0.97

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

D;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;T

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.21

MutPred

0.29

Loss of solvent accessibility (P = 0.0146);.;

MVP

0.85

MPC

0.37

ClinPred

0.47

GERP RS

3.1

Varity_R

0.19

gMVP

0.32

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