rs9640663

chr7-77618504-G-Achr7-77618504-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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 -14 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 criteria_provided_single_submitter, 1 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	UniProt
PTPN12	NM_002835.4	c.964G>A	p.Val322Ile	missense_variant	12/18	ENST00000248594.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN12	ENST00000248594.11	c.964G>A	p.Val322Ile	missense_variant	12/18	1	NM_002835.4	P1
PTPN12	ENST00000415482.6	c.607G>A	p.Val203Ile	missense_variant	12/18	5
PTPN12	ENST00000435495.6	c.574G>A	p.Val192Ile	missense_variant	11/17	2

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: criteria provided, single submitter

Submissions by phenotype

PTPN12-related disorder Benign:1

Benign, criteria provided, single submitter

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;