7-77627396-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002835.4(PTPN12):​c.1717A>C​(p.Thr573Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T573A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN12 NM_002835.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026507795).

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>C	p.Thr573Pro	missense	Exon 13 of 18	NP_002826.3
	PTPN12	NM_001131008.2		c.1360A>C	p.Thr454Pro	missense	Exon 13 of 18	NP_001124480.1
	PTPN12	NM_001131009.2		c.1327A>C	p.Thr443Pro	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>C	p.Thr573Pro	missense	Exon 13 of 18	ENSP00000248594.6
	PTPN12	ENST00000415482.6	TSL:5	c.1360A>C	p.Thr454Pro	missense	Exon 13 of 18	ENSP00000392429.2
	PTPN12	ENST00000435495.6	TSL:2	c.1327A>C	p.Thr443Pro	missense	Exon 12 of 17	ENSP00000397991.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.1
DANN	Benign	0.58
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
PhyloP100		-0.24
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.063
Sift	Benign	0.45	T
Sift4G	Benign	0.28	T
Polyphen		0.0030	B
Vest4		0.063
MutPred		0.074		Gain of catalytic residue at P572 (P = 0.0393)
MVP		0.44
MPC		0.027
ClinPred		0.050	T
GERP RS		-0.39
PromoterAI		0.0062	Neutral
Varity_R		0.051
gMVP		0.065
Mutation Taster		=99/1	polymorphism

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;