20-3022822-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_001385305.1(PTPRA):c.1462G>A(p.Asp488Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTPRA NM_001385305.1 missense, splice_region
• Scores: Splicing: ADA: 0.9659
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

Genes affected

PTPRA (HGNC:9664): (protein tyrosine phosphatase receptor type A) 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 contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. This PTP has been shown to dephosphorylate and activate Src family tyrosine kinases, and is implicated in the regulation of integrin signaling, cell adhesion and proliferation. Three alternatively spliced variants of this gene, which encode two distinct isoforms, have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTPRA
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRA	NM_001385305.1	c.1462G>A	p.Asp488Asn	missense_variant, splice_region_variant	16/24	ENST00000399903.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRA	ENST00000399903.7	c.1462G>A	p.Asp488Asn	missense_variant, splice_region_variant	16/24	5	NM_001385305.1	P4
PTPRA	ENST00000216877.10	c.1435G>A	p.Asp479Asn	missense_variant, splice_region_variant	15/23	1		A1
PTPRA	ENST00000356147.3	c.1435G>A	p.Asp479Asn	missense_variant, splice_region_variant	15/23	1		A1
PTPRA	ENST00000318266.9	c.1435G>A	p.Asp479Asn	missense_variant, splice_region_variant	16/24	5		A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Feb 27, 2023

The c.1462G>A (p.D488N) alteration is located in exon 20 (coding exon 13) of the PTPRA gene. This alteration results from a G to A substitution at nucleotide position 1462, causing the aspartic acid (D) at amino acid position 488 to be replaced by an asparagine (N). 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	0.93
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.93	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.96	D;.;D;.;.
Vest4		0.78
MVP		0.49
MPC		1.5
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.53
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.77
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

LitVar

Other links and lift over

dbSNP: rs1470811825; hg19: chr20-3003468; COSMIC: COSV53781188;