20-964075-T-G

Position:

chr20-964075-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001029871.4(RSPO4):c.455A>C(p.His152Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,613,792 control chromosomes in the GnomAD database, including 23 homozygotes. 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 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 22 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 1.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012876421).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00285 (434/152260) while in subpopulation NFE AF= 0.00484 (329/68014). AF 95% confidence interval is 0.00441. There are 1 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RSPO4	NM_001029871.4 linkuse as main transcript	c.455A>C	p.His152Pro	missense_variant	4/5	ENST00000217260.9	NP_001025042.2
RSPO4	XM_017027839.2 linkuse as main transcript	c.455A>C	p.His152Pro	missense_variant	4/4		XP_016883328.1
RSPO4	NM_001040007.3 linkuse as main transcript	c.409+3099A>C		intron_variant			NP_001035096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9 linkuse as main transcript	c.455A>C	p.His152Pro	missense_variant	4/5	1	NM_001029871.4	ENSP00000217260	P1	Q2I0M5-1
RSPO4	ENST00000400634.2 linkuse as main transcript	c.409+3099A>C		intron_variant		1		ENSP00000383475		Q2I0M5-2

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00484

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00307

AC:

760

AN:

247400

Hom.:

AF XY:

0.00298

AC XY:

402

AN XY:

134720

show subpopulations

Gnomad AFR exome

AF:

0.000533

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00370

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.000746

Gnomad NFE exome

AF:

0.00509

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00429

AC:

6264

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3005

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00253

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.000828

Gnomad4 NFE exome

AF:

0.00512

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.00285

AC:

434

AN:

152260

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00484

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.00301

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000529

AC:

ESP6500EA

AF:

0.00513

AC:

ExAC

AF:

0.00298

AC:

360

EpiCase

AF:

0.00485

EpiControl

AF:

0.00403

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.455A>C (p.H152P) alteration is located in exon 4 (coding exon 4) of the RSPO4 gene. This alteration results from a A to C substitution at nucleotide position 455, causing the histidine (H) at amino acid position 152 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

RSPO4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.33

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.29

Sift

Benign

0.040

Sift4G

Benign

0.20

Polyphen

0.92

Vest4

0.52

MVP

0.72

MPC

0.078

ClinPred

0.043

GERP RS

3.8

Varity_R

0.24

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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