20-963959-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.337

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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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 GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO4	NM_001029871.4	c.571C>T	p.Pro191Ser	missense_variant	4/5	ENST00000217260.9
RSPO4	XM_017027839.2	c.571C>T	p.Pro191Ser	missense_variant	4/4
RSPO4	NM_001040007.3	c.409+3215C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO4	ENST00000217260.9	c.571C>T	p.Pro191Ser	missense_variant	4/5	1	NM_001029871.4	P1
RSPO4	ENST00000400634.2	c.409+3215C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152222 Hom.: 4 Cov.: 32

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.: 1 AF XY: 0.000480 AC XY: 65 AN XY: 135360

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.: 0 Cov.: 32 AF XY: 0.000227 AC XY: 165 AN XY: 727156

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.: 5 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74496

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.: 0

Bravo AF: 0.00335

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00696 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000769 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RSPO4-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	16
Dann	Benign	0.90
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.095
Sift	Benign	0.44	T
Sift4G	Benign	0.63	T
Polyphen		0.0030	B
Vest4		0.29
MVP		0.40
MPC		0.054
ClinPred		0.0039	T
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

Other links and lift over

dbSNP: rs138935370; hg19: chr20-944602;