6-127195877-A-C

Position:

• chr6-127195877-A-C

Variant summary

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

The NM_032784.5(RSPO3):​c.689A>C​(p.Glu230Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPO3 NM_032784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

Genes affected

RSPO3 (HGNC:20866): (R-spondin 3) This gene belongs to the R-spondin family. The encoded protein plays a role in the regulation of Wnt (wingless-type MMTV integration site family)/beta-catenin and Wnt/planar cell polarity (PCP) signaling pathways, which are involved in development, cell growth and disease pathogenesis. Genome-wide association studies suggest a correlation of this gene with bone mineral density and risk of fracture. This gene may be involved in tumor development. [provided by RefSeq, Jul 2013]

LOC105377989 (HGNC:):

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=0.1399315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPO3	NM_032784.5	c.689A>C	p.Glu230Ala	missense_variant	5/5	ENST00000356698.9	NP_116173.2
LOC105377989	XR_002956387.2	n.113-15881T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPO3	ENST00000356698.9	c.689A>C	p.Glu230Ala	missense_variant	5/5	1	NM_032784.5	ENSP00000349131	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.689A>C (p.E230A) alteration is located in exon 5 (coding exon 5) of the RSPO3 gene. This alteration results from a A to C substitution at nucleotide position 689, causing the glutamic acid (E) at amino acid position 230 to be replaced by an alanine (A). 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	Benign	0.10
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.083	B;P
Vest4		0.12
MutPred		0.17		Gain of MoRF binding (P = 0.0267);Gain of MoRF binding (P = 0.0267);
MVP		0.74
MPC		0.59
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.13
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-127517022;