rs3750050

Positions:

• chr7-77627396-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000248594.11(PTPN12):​c.1717A>G​(p.Thr573Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,716 control chromosomes in the GnomAD database, including 41,036 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 0.22 (4724 hom., cov: 32)
  • Exomes 𝑓: 0.19 (36312 hom.)
• Consequence: PTPN12 ENST00000248594.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.243

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5089885E-6).
• BP6: Variant 7-77627396-A-G is Benign according to our data. Variant chr7-77627396-A-G is described in ClinVar as [Benign]. Clinvar id is 1235641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN12	NM_002835.4	c.1717A>G	p.Thr573Ala	missense_variant	13/18	ENST00000248594.11	NP_002826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN12	ENST00000248594.11	c.1717A>G	p.Thr573Ala	missense_variant	13/18	1	NM_002835.4	ENSP00000248594	P1
PTPN12	ENST00000415482.6	c.1360A>G	p.Thr454Ala	missense_variant	13/18	5		ENSP00000392429
PTPN12	ENST00000435495.6	c.1327A>G	p.Thr443Ala	missense_variant	12/17	2		ENSP00000397991
PTPN12	ENST00000407343.3	c.241A>G	p.Thr81Ala	missense_variant	1/4	3		ENSP00000385079

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33396 AN: 152040 Hom.: 4722 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.251

GnomAD3 exomes AF: 0.270 AC: 67842 AN: 251242 Hom.: 12860 AF XY: 0.265 AC XY: 36009 AN XY: 135798

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.710

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.190 AC: 278324 AN: 1461558 Hom.: 36312 Cov.: 34 AF XY: 0.194 AC XY: 141402 AN XY: 727098

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.711

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.220 AC: 33406 AN: 152158 Hom.: 4724 Cov.: 32 AF XY: 0.229 AC XY: 17015 AN XY: 74392

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.251

Alfa AF: 0.185 Hom.: 8610

Bravo AF: 0.235

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.152 AC: 585

ESP6500AA AF: 0.215 AC: 949

ESP6500EA AF: 0.152 AC: 1303

ExAC AF: 0.261 AC: 31702

Asia WGS AF: 0.484 AC: 1683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 30731403) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PTPN12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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	0.058
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.3
DANN	Benign	0.59
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.53	T;T;T;T
MetaRNN	Benign	0.0000025	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.87	N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.010
MPC		0.024
ClinPred		0.0037	T
GERP RS		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.12

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: rs3750050; hg19: chr7-77256713; COSMIC: COSV50354006;