chr2-219295035-A-T

Variant names:

• chr2-219295035-A-T
• NM_002846.4:c.2615T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002846.4(PTPRN):​c.2615T>A​(p.Phe872Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F872L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPRN NM_002846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

Genes affected

PTPRN (HGNC:9676): (protein tyrosine phosphatase receptor type N) 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 catalytic domain, and thus represents a receptor-type PTP. This PTP was found to be an autoantigen that is reactive with insulin-dependent diabetes mellitus (IDDM) patient sera, and thus may be a potential target of autoimmunity in diabetes mellitus. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40632185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRN	NM_002846.4	c.2615T>A	p.Phe872Tyr	missense_variant	Exon 19 of 23	ENST00000295718.7	NP_002837.1
PTPRN	NM_001199763.2	c.2528T>A	p.Phe843Tyr	missense_variant	Exon 18 of 22		NP_001186692.1
PTPRN	NM_001199764.2	c.2345T>A	p.Phe782Tyr	missense_variant	Exon 19 of 23		NP_001186693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRN	ENST00000295718.7	c.2615T>A	p.Phe872Tyr	missense_variant	Exon 19 of 23	1	NM_002846.4	ENSP00000295718.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2615T>A (p.F872Y) alteration is located in exon 19 (coding exon 19) of the PTPRN gene. This alteration results from a T to A substitution at nucleotide position 2615, causing the phenylalanine (F) at amino acid position 872 to be replaced by a tyrosine (Y). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.17	.;N;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Benign	0.22
Sift	Benign	0.11	T;D;.
Sift4G	Benign	0.064	T;T;T
Polyphen		0.15	.;B;.
Vest4		0.46
MutPred		0.79		.;Gain of phosphorylation at F872 (P = 0.0714);.;
MVP		0.061
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.60
Mutation Taster		=41/59	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: chr2-220159757;