Genetic Variant NM_002840.5:c.1847_1848delTG (chr1-43597774-ATG-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_002840.5(PTPRF):c.1847_1848delTG(p.Val616GlufsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,288,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

PTPRF
NM_002840.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.948

Publications

2 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae)

PTPRF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-43597774-ATG-A is Pathogenic according to our data. Variant chr1-43597774-ATG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 155912.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTPRF	NM_002840.5	MANE Select	c.1847_1848delTG	p.Val616GlufsTer49	frameshift	Exon 12 of 34	NP_002831.2
PTPRF	NM_130440.4		c.1847_1848delTG	p.Val616GlufsTer49	frameshift	Exon 12 of 33	NP_569707.2
PTPRF	NM_001329138.2		c.1844-939_1844-938delTG		intron	N/A	NP_001316067.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTPRF	ENST00000359947.9	TSL:1 MANE Select	c.1847_1848delTG	p.Val616GlufsTer49	frameshift	Exon 12 of 34	ENSP00000353030.4
PTPRF	ENST00000438120.5	TSL:1	c.1847_1848delTG	p.Val616GlufsTer49	frameshift	Exon 12 of 33	ENSP00000398822.1
PTPRF	ENST00000429895.5	TSL:1	c.815_816delTG	p.Val272fs	frameshift	Exon 4 of 25	ENSP00000408952.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.76e-7

AC:

AN:

1288990

Hom.:

AF XY:

0.00000156

AC XY:

AN XY:

640480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29064

American (AMR)

AF:

0.00

AC:

AN:

39434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20896

East Asian (EAS)

AF:

0.00

AC:

AN:

27166

South Asian (SAS)

AF:

0.00

AC:

AN:

82072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36788

Middle Eastern (MID)

AF:

0.000203

AC:

AN:

4920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

998372

Other (OTH)

AF:

0.00

AC:

AN:

50278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breasts and/or nipples, aplasia or hypoplasia of, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.95

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over