rs9640663

Positions:

• chr7-77618504-G-A
• chr7-77618504-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002835.4(PTPN12):​c.964G>A​(p.Val322Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,597,548 control chromosomes in the GnomAD database, including 315,015 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.69 (36948 hom., cov: 31)
  • Exomes 𝑓: 0.61 (278067 hom.)
• Consequence: PTPN12 NM_002835.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.40

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.785749E-7).
• BP6: Variant 7-77618504-G-A is Benign according to our data. Variant chr7-77618504-G-A is described in ClinVar as [Benign]. Clinvar id is 3060850.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN12	NM_002835.4	c.964G>A	p.Val322Ile	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.964G>A	p.Val322Ile	missense_variant	12/18	1	NM_002835.4	ENSP00000248594	P1
PTPN12	ENST00000415482.6	c.607G>A	p.Val203Ile	missense_variant	12/18	5		ENSP00000392429
PTPN12	ENST00000435495.6	c.574G>A	p.Val192Ile	missense_variant	11/17	2		ENSP00000397991

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104266 AN: 151808 Hom.: 36898 Cov.: 31

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.693

GnomAD3 exomes AF: 0.673 AC: 166984 AN: 248078 Hom.: 57955 AF XY: 0.663 AC XY: 88938 AN XY: 134174

Gnomad AFR exome AF: 0.831

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.899

Gnomad SAS exome AF: 0.686

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.614 AC: 888205 AN: 1445622 Hom.: 278067 Cov.: 32 AF XY: 0.615 AC XY: 442508 AN XY: 719362

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.804

Gnomad4 ASJ exome AF: 0.679

Gnomad4 EAS exome AF: 0.920

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.645

GnomAD4 genome AF: 0.687 AC: 104374 AN: 151926 Hom.: 36948 Cov.: 31 AF XY: 0.687 AC XY: 51049 AN XY: 74256

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.902

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.588

Gnomad4 OTH AF: 0.693

Alfa AF: 0.615 Hom.: 52116

Bravo AF: 0.706

TwinsUK AF: 0.590 AC: 2187

ALSPAC AF: 0.581 AC: 2238

ESP6500AA AF: 0.827 AC: 3643

ESP6500EA AF: 0.587 AC: 5049

ExAC AF: 0.672 AC: 81569

Asia WGS AF: 0.820 AC: 2851 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PTPN12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as 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	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	6.8e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.;.
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.028
MPC		0.022
ClinPred		0.0057	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs9640663; hg19: chr7-77247821; COSMIC: COSV50354232;