20-3027761-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001385305.1(PTPRA):c.1840A>G(p.Ile614Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,614,066 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (3 hom.)
• Consequence: PTPRA NM_001385305.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTPRA
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRA	NM_001385305.1	c.1840A>G	p.Ile614Val	missense_variant	20/24	ENST00000399903.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRA	ENST00000399903.7	c.1840A>G	p.Ile614Val	missense_variant	20/24	5	NM_001385305.1	P4
PTPRA	ENST00000216877.10	c.1813A>G	p.Ile605Val	missense_variant	19/23	1		A1
PTPRA	ENST00000356147.3	c.1813A>G	p.Ile605Val	missense_variant	19/23	1		A1
PTPRA	ENST00000318266.9	c.1813A>G	p.Ile605Val	missense_variant	20/24	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251412 Hom.: 2 AF XY: 0.000243 AC XY: 33 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.0000759 AC: 111 AN: 1461858 Hom.: 3 Cov.: 31 AF XY: 0.0000990 AC XY: 72 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 1

Bravo AF: 0.0000189

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jan 22, 2024

The c.1840A>G (p.I614V) alteration is located in exon 24 (coding exon 17) of the PTPRA gene. This alteration results from a A to G substitution at nucleotide position 1840, causing the isoleucine (I) at amino acid position 614 to be replaced by a valine (V). 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	Benign	0.058
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Benign	0.66
DEOGEN2	Benign	0.31	T;.;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.4	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.65	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.
Vest4		0.14
MVP		0.40
MPC		0.54
ClinPred		0.047	T
GERP RS		5.6
Varity_R		0.071
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs774971415; hg19: chr20-3008407;