Variant chr20-960442-C-T 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.620G>A(p.Gly207Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000461 in 1,539,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.801

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=0.122752815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO4	NM_001029871.4 linkuse as main transcript	c.620G>A	p.Gly207Asp	missense_variant	5/5	ENST00000217260.9
RSPO4	NM_001040007.3 linkuse as main transcript	c.434G>A	p.Gly145Asp	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO4	ENST00000217260.9 linkuse as main transcript	c.620G>A	p.Gly207Asp	missense_variant	5/5	1	NM_001029871.4	P1	Q2I0M5-1
RSPO4	ENST00000400634.2 linkuse as main transcript	c.434G>A	p.Gly145Asp	missense_variant	4/4	1			Q2I0M5-2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000416

AC:

AN:

144394

Hom.:

AF XY:

0.0000388

AC XY:

AN XY:

77278

show subpopulations

Gnomad AFR exome

AF:

0.000755

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000259

AC:

AN:

1387348

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

684750

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000271

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.000230

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000956

Bravo

AF:

0.000261

ExAC

AF:

0.0000111

AC:

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

Jan 23, 2024

The c.620G>A (p.G207D) 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 620, causing the glycine (G) at amino acid position 207 to be replaced by an aspartic acid (D). 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

0.098

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.69

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.90

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

N;D

REVEL

Benign

0.28

Sift

Benign

0.070

T;D

Sift4G

Benign

0.12

T;D

Polyphen

0.99

D;P

Vest4

0.21

MVP

0.76

MPC

0.38

ClinPred

0.15

GERP RS

3.8

Varity_R

0.088

gMVP

0.20

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