20-964075-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (22 hom.)
• Consequence: RSPO4 NM_001029871.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.18

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012876421).
• BP6: Variant 20-964075-T-G is Benign according to our data. Variant chr20-964075-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2352533.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO4	NM_001029871.4	c.455A>C	p.His152Pro	missense_variant	4/5	ENST00000217260.9
RSPO4	XM_017027839.2	c.455A>C	p.His152Pro	missense_variant	4/4
RSPO4	NM_001040007.3	c.409+3099A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO4	ENST00000217260.9	c.455A>C	p.His152Pro	missense_variant	4/5	1	NM_001029871.4	P1
RSPO4	ENST00000400634.2	c.409+3099A>C		intron_variant		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

GnomAD3 exomes AF: 0.00307 AC: 760 AN: 247400 Hom.: 2 AF XY: 0.00298 AC XY: 402 AN XY: 134720

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 SAS exome AF: 0.00137

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

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.000828

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00331

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

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00410 Hom.: 2

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.455A>C (p.H152P) alteration is located in exon 4 (coding exon 4) of the RSPO4 gene. This alteration results from a A to C substitution at nucleotide position 455, causing the histidine (H) at amino acid position 152 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RSPO4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs191521473; hg19: chr20-944718;