7-77627396-A-G

Variant names:

• chr7-77627396-A-G
• rs3750050
• NM_002835.4:c.1717A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002835.4(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4724 hom., cov: 32)
  • Exomes 𝑓: 0.19 (36312 hom.)
• Consequence: PTPN12 NM_002835.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.243
• Publications: 38 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002835.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN12	NM_002835.4	MANE Select	c.1717A>G	p.Thr573Ala	missense	Exon 13 of 18	NP_002826.3
	PTPN12	NM_001131008.2		c.1360A>G	p.Thr454Ala	missense	Exon 13 of 18	NP_001124480.1
	PTPN12	NM_001131009.2		c.1327A>G	p.Thr443Ala	missense	Exon 12 of 17	NP_001124481.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN12	ENST00000248594.11	TSL:1 MANE Select	c.1717A>G	p.Thr573Ala	missense	Exon 13 of 18	ENSP00000248594.6
	PTPN12	ENST00000415482.6	TSL:5	c.1360A>G	p.Thr454Ala	missense	Exon 13 of 18	ENSP00000392429.2
	PTPN12	ENST00000435495.6	TSL:2	c.1327A>G	p.Thr443Ala	missense	Exon 12 of 17	ENSP00000397991.2

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

GnomAD2 exomes AF: 0.270 AC: 67842 AN: 251242 AF XY: 0.265

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 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

African (AFR) AF: 0.209 AC: 7004 AN: 33470

American (AMR) AF: 0.445 AC: 19921 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4713 AN: 26130

East Asian (EAS) AF: 0.711 AC: 28232 AN: 39696

South Asian (SAS) AF: 0.353 AC: 30415 AN: 86242

European-Finnish (FIN) AF: 0.165 AC: 8829 AN: 53390

Middle Eastern (MID) AF: 0.257 AC: 1480 AN: 5768

European-Non Finnish (NFE) AF: 0.148 AC: 164579 AN: 1111754

Other (OTH) AF: 0.218 AC: 13151 AN: 60388

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

African (AFR) AF: 0.211 AC: 8761 AN: 41516

American (AMR) AF: 0.357 AC: 5447 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3470

East Asian (EAS) AF: 0.704 AC: 3646 AN: 5178

South Asian (SAS) AF: 0.367 AC: 1769 AN: 4820

European-Finnish (FIN) AF: 0.169 AC: 1789 AN: 10592

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10588 AN: 67992

Other (OTH) AF: 0.251 AC: 531 AN: 2116

Alfa AF: 0.190 Hom.: 13677

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30731403)

PTPN12-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.24
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.030
Sift	Benign	0.29	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.010
MPC		0.024
ClinPred		0.0037	T
GERP RS		-0.39
PromoterAI		0.0013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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