NM_001029871.4:c.455A>C

Variant names:

• chr20-964075-T-G
• rs191521473
• NM_001029871.4:c.455A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001029871.4(RSPO4):​c.455A>C​(p.His152Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,613,792 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (22 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: 1.18
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012876421).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00285 (434/152260) while in subpopulation NFE AF = 0.00484 (329/68014). AF 95% confidence interval is 0.00441. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

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.455A>C	p.His152Pro	missense	Exon 4 of 5	NP_001025042.2	Q2I0M5-1
	RSPO4	NM_001040007.3		c.409+3099A>C		intron	N/A	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.455A>C	p.His152Pro	missense	Exon 4 of 5	ENSP00000217260.4	Q2I0M5-1
	RSPO4	ENST00000400634.2	TSL:1	c.409+3099A>C		intron	N/A	ENSP00000383475.2	Q2I0M5-2
	RSPO4	ENST00000873320.1		c.425A>C	p.His142Pro	missense	Exon 4 of 5	ENSP00000543379.1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00307 AC: 760 AN: 247400 AF XY: 0.00298

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000746

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00429 AC: 6264 AN: 1461532 Hom.: 22 Cov.: 32 AF XY: 0.00413 AC XY: 3005 AN XY: 727092

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00121 AC: 104 AN: 86242

European-Finnish (FIN) AF: 0.000828 AC: 44 AN: 53130

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00512 AC: 5693 AN: 1111982

Other (OTH) AF: 0.00331 AC: 200 AN: 60392

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74442

African (AFR) AF: 0.000770 AC: 32 AN: 41554

American (AMR) AF: 0.00274 AC: 42 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00484 AC: 329 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00395 Hom.: 4

Bravo AF: 0.00301

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000529 AC: 2

ESP6500EA AF: 0.00513 AC: 42

ExAC AF: 0.00298 AC: 360

EpiCase AF: 0.00485

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	RSPO4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.29
Sift	Benign	0.040	D
Sift4G	Benign	0.20	T
Polyphen		0.92	P
Vest4		0.52
MVP		0.72
MPC		0.078
ClinPred		0.043	T
GERP RS		3.8
Varity_R		0.24
gMVP		0.45
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs191521473; hg19: chr20-944718;