chr7-77618555-A-G

Position:

• chr7-77618555-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002835.4(PTPN12):​c.1015A>G​(p.Arg339Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN12 NM_002835.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

PTPN12 (HGNC:9645): (protein tyrosine phosphatase non-receptor type 12) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains a C-terminal PEST motif, which serves as a protein-protein interaction domain, and may regulate protein intracellular half-life. This PTP was found to bind and dephosphorylate the product of the oncogene c-ABL and thus may play a role in oncogenesis. This PTP was also shown to interact with, and dephosphorylate, various products related to cytoskeletal structure and cell adhesion, such as p130 (Cas), CAKbeta/PTK2B, PSTPIP1, and paxillin. This suggests it has a regulatory role in controlling cell shape and mobility. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN12	NM_002835.4	c.1015A>G	p.Arg339Gly	missense_variant	12/18	ENST00000248594.11	NP_002826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN12	ENST00000248594.11	c.1015A>G	p.Arg339Gly	missense_variant	12/18	1	NM_002835.4	ENSP00000248594.6
PTPN12	ENST00000415482.6	c.658A>G	p.Arg220Gly	missense_variant	12/18	5		ENSP00000392429.2
PTPN12	ENST00000435495.6	c.625A>G	p.Arg209Gly	missense_variant	11/17	2		ENSP00000397991.2

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

Aug 12, 2024

The c.1015A>G (p.R339G) alteration is located in exon 12 (coding exon 12) of the PTPN12 gene. This alteration results from a A to G substitution at nucleotide position 1015, causing the arginine (R) at amino acid position 339 to be replaced by a glycine (G). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.26		Loss of solvent accessibility (P = 0.0159);.;.;
MVP		0.61
MPC		0.15
ClinPred		0.98	D
GERP RS		0.88
Varity_R		0.56
gMVP		0.48

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: chr7-77247872;