chr1-43569658-C-T

Variant names:

• chr1-43569658-C-T
• NM_002840.5:c.448C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002840.5(PTPRF):​c.448C>T​(p.Arg150Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PTPRF NM_002840.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• breasts and/or nipples, aplasia or hypoplasia of, 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002840.5. 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
	PTPRF	NM_002840.5	MANE Select	c.448C>T	p.Arg150Cys	missense	Exon 6 of 34	NP_002831.2	P10586-1
	PTPRF	NM_130440.4		c.448C>T	p.Arg150Cys	missense	Exon 6 of 33	NP_569707.2	P10586-2
	PTPRF	NM_001329138.2		c.448C>T	p.Arg150Cys	missense	Exon 7 of 37	NP_001316067.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRF	ENST00000359947.9	TSL:1 MANE Select	c.448C>T	p.Arg150Cys	missense	Exon 6 of 34	ENSP00000353030.4	P10586-1
	PTPRF	ENST00000438120.5	TSL:1	c.448C>T	p.Arg150Cys	missense	Exon 6 of 33	ENSP00000398822.1	P10586-2
	PTPRF	ENST00000437607.1	TSL:1	c.448C>T	p.Arg150Cys	missense	Exon 4 of 6	ENSP00000413306.1	A2A437

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461668 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727138

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.56		Loss of ubiquitination at K148 (P = 0.057)
MVP		0.61
MPC		1.9
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.85
Mutation Taster		=42/58	disease causing

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

hg19: chr1-44035329;