1-43578899-C-T

Position:

• chr1-43578899-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002840.5(PTPRF):​c.658C>T​(p.Pro220Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTPRF NM_002840.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

PTPRF (HGNC:9670): (protein tyrosine phosphatase receptor type F) 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 two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region contains three Ig-like domains, and nine non-Ig like domains similar to that of neural-cell adhesion molecule. This PTP was shown to function in the regulation of epithelial cell-cell contacts at adherents junctions, as well as in the control of beta-catenin signaling. An increased expression level of this protein was found in the insulin-responsive tissue of obese, insulin-resistant individuals, and may contribute to the pathogenesis of insulin resistance. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

PTPRF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPRF. . Gene score misZ 2.7957 (greater than the threshold 3.09). Trascript score misZ 4.0463 (greater than threshold 3.09). GenCC has associacion of gene with breasts and/or nipples, aplasia or hypoplasia of, 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38662526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPRF	NM_002840.5	c.658C>T	p.Pro220Ser	missense_variant	7/34	ENST00000359947.9	NP_002831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPRF	ENST00000359947.9	c.658C>T	p.Pro220Ser	missense_variant	7/34	1	NM_002840.5	ENSP00000353030.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jan 31, 2022

The c.658C>T (p.P220S) alteration is located in exon 7 (coding exon 5) of the PTPRF gene. This alteration results from a C to T substitution at nucleotide position 658, causing the proline (P) at amino acid position 220 to be replaced by a serine (S). 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	Pathogenic	0.65
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	.;D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.29	.;N;N;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.1	.;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.11	.;T;T;T
Sift4G	Uncertain	0.013	D;T;T;D
Polyphen		1.0	.;D;D;.
Vest4		0.77
MutPred		0.33		Gain of MoRF binding (P = 0.0546);Gain of MoRF binding (P = 0.0546);Gain of MoRF binding (P = 0.0546);Gain of MoRF binding (P = 0.0546);
MVP		0.44
MPC		1.7
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.40
gMVP		0.67

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: chr1-44044570; COSMIC: COSV63445708; COSMIC: COSV63445708;