Variant 20-963959-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001029871.4(RSPO4):c.571C>T(p.Pro191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,614,042 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

RSPO4
NM_001029871.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.337

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070375204).

BP6

Variant 20-963959-G-A is Benign according to our data. Variant chr20-963959-G-A is described in ClinVar as [Benign]. Clinvar id is 3040155.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00299 (455/152340) while in subpopulation AFR AF= 0.0104 (434/41570). AF 95% confidence interval is 0.00963. There are 5 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RSPO4	NM_001029871.4 linkuse as main transcript	c.571C>T	p.Pro191Ser	missense_variant	4/5	ENST00000217260.9	NP_001025042.2
RSPO4	XM_017027839.2 linkuse as main transcript	c.571C>T	p.Pro191Ser	missense_variant	4/4		XP_016883328.1
RSPO4	NM_001040007.3 linkuse as main transcript	c.409+3215C>T		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.571C>T	p.Pro191Ser	missense_variant	4/5	1	NM_001029871.4	ENSP00000217260	P1	Q2I0M5-1
RSPO4	ENST00000400634.2 linkuse as main transcript	c.409+3215C>T		intron_variant		1		ENSP00000383475		Q2I0M5-2

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

448

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.00191

GnomAD3 exomes

AF:

0.000641

AC:

160

AN:

249430

Hom.:

AF XY:

0.000480

AC XY:

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.00872

Gnomad AMR exome

AF:

0.000637

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:

0.00000884

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00989

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.00299

AC:

455

AN:

152340

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

213

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.00111

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:

0.00189

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.00335

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00696

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000769

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RSPO4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as 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

0.092

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.047

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.050

REVEL

Benign

0.095

Sift

Benign

0.44

Sift4G

Benign

0.63

Polyphen

0.0030

Vest4

0.29

MVP

0.40

MPC

0.054

ClinPred

0.0039

GERP RS

-0.54

Varity_R

0.027

gMVP

0.35

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