rs775644973

chr20-1002085-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_001029871.4(RSPO4):c.79+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000893 in 1,556,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: RSPO4 NM_001029871.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.50

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 Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-1002085-C-T is Pathogenic according to our data. Variant chr20-1002085-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 521270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO4	NM_001029871.4	c.79+1G>A		splice_donor_variant		ENST00000217260.9
RSPO4	NM_001040007.3	c.79+1G>A		splice_donor_variant
RSPO4	XM_017027839.2	c.79+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO4	ENST00000217260.9	c.79+1G>A		splice_donor_variant		1	NM_001029871.4	P1
RSPO4	ENST00000400634.2	c.79+1G>A		splice_donor_variant		1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000814 AC: 13 AN: 159736 Hom.: 0 AF XY: 0.0000813 AC XY: 7 AN XY: 86130

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.0000775

Gnomad ASJ exome AF: 0.000585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000647

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 119 AN: 1403924 Hom.: 1 Cov.: 30 AF XY: 0.0000894 AC XY: 62 AN XY: 693426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000814

Gnomad4 ASJ exome AF: 0.000358

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000627

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.0000860

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000353 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anonychia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2022

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22300369, 17805348, 17186469, 17914448, 34426522, 31589614, 23234511, 34582790, 17041604) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -8
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775644973; hg19: chr20-982728;