chr12-15484018-C-G

Variant names:

• chr12-15484018-C-G
• rs1395692706
• NM_030667.3:c.120C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030667.3(PTPRO):​c.120C>G​(p.Ile40Met) 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 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I40I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPRO NM_030667.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• Publications: 0 publications found

Genes affected

PTPRO (HGNC:9678): (protein tyrosine phosphatase receptor type O) This gene encodes a member of the R3 subtype family of receptor-type protein tyrosine phosphatases. These proteins are localized to the apical surface of polarized cells and may have tissue-specific functions through activation of Src family kinases. This gene contains two distinct promoters, and alternatively spliced transcript variants encoding multiple isoforms have been observed. The encoded proteins may have multiple isoform-specific and tissue-specific functions, including the regulation of osteoclast production and activity, inhibition of cell proliferation and facilitation of apoptosis. This gene is a candidate tumor suppressor, and decreased expression of this gene has been observed in several types of cancer. [provided by RefSeq, May 2011]

PTPRO Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 6

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37632483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRO	NM_030667.3	c.120C>G	p.Ile40Met	missense_variant	Exon 2 of 27	ENST00000281171.9	NP_109592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRO	ENST00000281171.9	c.120C>G	p.Ile40Met	missense_variant	Exon 2 of 27	1	NM_030667.3	ENSP00000281171.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461334 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111556

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.63	N;N;N
PhyloP100		0.022
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.72	P;.;P
Vest4		0.60
MutPred		0.44		Gain of catalytic residue at V42 (P = 9e-04);Gain of catalytic residue at V42 (P = 9e-04);Gain of catalytic residue at V42 (P = 9e-04);
MVP		0.29
MPC		0.57
ClinPred		0.42	T
GERP RS		1.0
Varity_R		0.098
gMVP		0.59
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1395692706; hg19: chr12-15636952;