20-964098-C-A

Variant names:

• chr20-964098-C-A
• rs1984103732
• NM_001029871.4:c.432G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001029871.4(RSPO4):​c.432G>T​(p.Trp144Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO4	NM_001029871.4	c.432G>T	p.Trp144Cys	missense_variant	Exon 4 of 5	ENST00000217260.9	NP_001025042.2
RSPO4	XM_017027839.2	c.432G>T	p.Trp144Cys	missense_variant	Exon 4 of 4		XP_016883328.1
RSPO4	NM_001040007.3	c.409+3076G>T		intron_variant	Intron 3 of 3		NP_001035096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9	c.432G>T	p.Trp144Cys	missense_variant	Exon 4 of 5	1	NM_001029871.4	ENSP00000217260.4
RSPO4	ENST00000400634.2	c.409+3076G>T		intron_variant	Intron 3 of 3	1		ENSP00000383475.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460768 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726648

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.432G>T (p.W144C) alteration is located in exon 4 (coding exon 4) of the RSPO4 gene. This alteration results from a G to T substitution at nucleotide position 432, causing the tryptophan (W) at amino acid position 144 to be replaced by a cysteine (C). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.63		Gain of catalytic residue at P143 (P = 0.0072);
MVP		0.81
MPC		0.42
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.66
gMVP		0.72

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: rs1984103732; hg19: chr20-944741;