chr20-960389-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic congenital nail disorder 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029871.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO4	NM_001029871.4	MANE Select	c.673G>A	p.Val225Met	missense	Exon 5 of 5	NP_001025042.2	Q2I0M5-1
	RSPO4	NM_001040007.3		c.487G>A	p.Val163Met	missense	Exon 4 of 4	NP_001035096.1	Q2I0M5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO4	ENST00000217260.9	TSL:1 MANE Select	c.673G>A	p.Val225Met	missense	Exon 5 of 5	ENSP00000217260.4	Q2I0M5-1
	RSPO4	ENST00000400634.2	TSL:1	c.487G>A	p.Val163Met	missense	Exon 4 of 4	ENSP00000383475.2	Q2I0M5-2
	RSPO4	ENST00000873320.1		c.643G>A	p.Val215Met	missense	Exon 5 of 5	ENSP00000543379.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31628

American (AMR) AF: 0.00 AC: 0 AN: 35872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35806

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1079276

Other (OTH) AF: 0.0000173 AC: 1 AN: 57918

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.88
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.064	T
Polyphen		0.87	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs768182696; hg19: chr20-941032;