chr1-43597774-ATG-A

Variant names:

• chr1-43597774-ATG-A
• rs1131692054
• NM_002840.5:c.1847_1848delTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.948
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1288990 Hom.: 0 AF XY: 0.00000156 AC XY: 1 AN XY: 640480

African (AFR) AF: 0.00 AC: 0 AN: 29064

American (AMR) AF: 0.00 AC: 0 AN: 39434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20896

East Asian (EAS) AF: 0.00 AC: 0 AN: 27166

South Asian (SAS) AF: 0.00 AC: 0 AN: 82072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36788

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4920

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 998372

Other (OTH) AF: 0.00 AC: 0 AN: 50278

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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)

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

Other links and lift over

dbSNP: rs1131692054; hg19: chr1-44063445;