12-70684260-T-A

Position:

• chr12-70684260-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002849.4(PTPRR):​c.1364A>T​(p.Tyr455Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPRR NM_002849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

PTPRR (HGNC:9680): (protein tyrosine phosphatase receptor type R) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and a single intracellular catalytic domain, and thus represents a receptor-type PTP. Silencing of this gene has been associated with colorectal cancer. Multiple transcript variants encoding different isoforms have been found for this gene. This gene shares a symbol (PTPRQ) with another gene, protein tyrosine phosphatase, receptor type, Q (GeneID 374462), which is also located on chromosome 12. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPRR	NM_002849.4	c.1364A>T	p.Tyr455Phe	missense_variant	10/14	ENST00000283228.7	NP_002840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPRR	ENST00000283228.7	c.1364A>T	p.Tyr455Phe	missense_variant	10/14	1	NM_002849.4	ENSP00000283228.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2022

The c.1364A>T (p.Y455F) alteration is located in exon 10 (coding exon 10) of the PTPRR gene. This alteration results from a A to T substitution at nucleotide position 1364, causing the tyrosine (Y) at amino acid position 455 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	.;.;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	.;D;T;D;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;.;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.051	T;T;T;D;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.83, 1.0	.;P;D;.;.
Vest4		0.73
MutPred		0.88		.;.;Loss of ubiquitination at K458 (P = 0.0566);.;.;
MVP		0.49
MPC		0.37
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.63
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-71078040;