20-960389-C-T

Variant names:

• chr20-960389-C-T
• rs768182696
• NM_001029871.4:c.673G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001029871.4(RSPO4):​c.673G>A​(p.Val225Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,538,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V225L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092871726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO4	NM_001029871.4	c.673G>A	p.Val225Met	missense_variant	Exon 5 of 5	ENST00000217260.9	NP_001025042.2
RSPO4	NM_001040007.3	c.487G>A	p.Val163Met	missense_variant	Exon 4 of 4		NP_001035096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO4	ENST00000217260.9	c.673G>A	p.Val225Met	missense_variant	Exon 5 of 5	1	NM_001029871.4	ENSP00000217260.4
RSPO4	ENST00000400634.2	c.487G>A	p.Val163Met	missense_variant	Exon 4 of 4	1		ENSP00000383475.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 20 AN: 1386138 Hom.: 0 Cov.: 31 AF XY: 0.0000102 AC XY: 7 AN XY: 684160

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.6
DANN	Benign	0.81
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.21
Sift	Benign	0.13	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.87	P;P
Vest4		0.070
MutPred		0.21		Gain of helix (P = 0.0854);.;
MVP		0.45
MPC		0.068
ClinPred		0.23	T
GERP RS		-0.038
Varity_R		0.025
gMVP		0.19

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: rs768182696; hg19: chr20-941032;