7-77618504-G-A

Variant names:

• chr7-77618504-G-A
• rs9640663
• NM_002835.4:c.964G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 44 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN12	NM_002835.4	MANE Select	c.964G>A	p.Val322Ile	missense	Exon 12 of 18	NP_002826.3
	PTPN12	NM_001131008.2		c.607G>A	p.Val203Ile	missense	Exon 12 of 18	NP_001124480.1	Q05209-3
	PTPN12	NM_001131009.2		c.574G>A	p.Val192Ile	missense	Exon 11 of 17	NP_001124481.1	Q05209-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN12	ENST00000248594.11	TSL:1 MANE Select	c.964G>A	p.Val322Ile	missense	Exon 12 of 18	ENSP00000248594.6	Q05209-1
	PTPN12	ENST00000962769.1		c.961G>A	p.Val321Ile	missense	Exon 12 of 18	ENSP00000632828.1
	PTPN12	ENST00000962770.1		c.793G>A	p.Val265Ile	missense	Exon 9 of 15	ENSP00000632829.1

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

GnomAD2 exomes AF: 0.673 AC: 166984 AN: 248078 AF XY: 0.663

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 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

African (AFR) AF: 0.834 AC: 27588 AN: 33060

American (AMR) AF: 0.804 AC: 35427 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17587 AN: 25888

East Asian (EAS) AF: 0.920 AC: 36211 AN: 39372

South Asian (SAS) AF: 0.677 AC: 57257 AN: 84516

European-Finnish (FIN) AF: 0.564 AC: 29860 AN: 52954

Middle Eastern (MID) AF: 0.662 AC: 3792 AN: 5728

European-Non Finnish (NFE) AF: 0.583 AC: 641986 AN: 1100354

Other (OTH) AF: 0.645 AC: 38497 AN: 59690

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

African (AFR) AF: 0.830 AC: 34421 AN: 41462

American (AMR) AF: 0.755 AC: 11529 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2376 AN: 3466

East Asian (EAS) AF: 0.902 AC: 4674 AN: 5180

South Asian (SAS) AF: 0.700 AC: 3371 AN: 4814

European-Finnish (FIN) AF: 0.550 AC: 5788 AN: 10516

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39919 AN: 67912

Other (OTH) AF: 0.693 AC: 1461 AN: 2108

Alfa AF: 0.627 Hom.: 75068

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PTPN12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	6.8e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.052
Sift	Benign	0.32	T
Sift4G	Benign	0.49	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
Mutation Taster		=92/8	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: rs9640663; hg19: chr7-77247821; COSMIC: COSV50354232;