12-15322750-A-G

Variant names:

• chr12-15322750-A-G
• NM_030667.3:c.24A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030667.3(PTPRO):​c.24A>G​(p.Ile8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I8L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPRO NM_030667.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.688

Genes affected

PTPRO (HGNC:9678): (protein tyrosine phosphatase receptor type O) This gene encodes a member of the R3 subtype family of receptor-type protein tyrosine phosphatases. These proteins are localized to the apical surface of polarized cells and may have tissue-specific functions through activation of Src family kinases. This gene contains two distinct promoters, and alternatively spliced transcript variants encoding multiple isoforms have been observed. The encoded proteins may have multiple isoform-specific and tissue-specific functions, including the regulation of osteoclast production and activity, inhibition of cell proliferation and facilitation of apoptosis. This gene is a candidate tumor suppressor, and decreased expression of this gene has been observed in several types of cancer. [provided by RefSeq, May 2011]

RERG (HGNC:15980): (RAS like estrogen regulated growth inhibitor) RERG, a member of the RAS superfamily of GTPases, inhibits cell proliferation and tumor formation (Finlin et al., 2001 [PubMed 11533059]).[supplied by OMIM, Mar 2009]

LOC105369673 (HGNC:):

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=0.06800455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRO	NM_030667.3	c.24A>G	p.Ile8Met	missense_variant	Exon 1 of 27	ENST00000281171.9	NP_109592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRO	ENST00000281171.9	c.24A>G	p.Ile8Met	missense_variant	Exon 1 of 27	1	NM_030667.3	ENSP00000281171.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.24A>G (p.I8M) alteration is located in exon 1 (coding exon 1) of the PTPRO gene. This alteration results from a A to G substitution at nucleotide position 24, causing the isoleucine (I) at amino acid position 8 to be replaced by a methionine (M). 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	0.092
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.8
DANN	Benign	0.35
DEOGEN2	Benign	0.097	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;N;N
PhyloP100		-0.69
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.056	T;T;D
Sift4G	Benign	0.092	T;T;T
Polyphen		0.051	B;.;B
Vest4		0.096
MutPred		0.27		Gain of catalytic residue at T6 (P = 0);Gain of catalytic residue at T6 (P = 0);Gain of catalytic residue at T6 (P = 0);
MVP		0.13
MPC		0.28
ClinPred		0.043	T
GERP RS		2.0
PromoterAI		-0.057	Neutral
Varity_R		0.066
gMVP		0.20
Mutation Taster		=98/2	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

Publications

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Other links and lift over

hg19: chr12-15475684; COSMIC: COSV99840591; COSMIC: COSV99840591;