Genetic Variant PTCRA:p.Arg187Cys (chr6-42925395-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138296.3(PTCRA):c.559C>T(p.Arg187Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,554,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 1 hom. )

Consequence

PTCRA
NM_138296.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.23

Variant links:

Genes affected

PTCRA (HGNC:21290): (pre T cell antigen receptor alpha) The protein encoded by this gene is a single-pass type I membrane protein that is found in immmature but not mature T-cells. Along with TCRB and CD3 complex, the encoded protein forms the pre-T-cell receptor complex, which regulates early T-cell development. Four transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

PTCRA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02732271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCRA	NM_138296.3 link	c.559C>T	p.Arg187Cys	missense_variant	Exon 4 of 4	ENST00000304672.6	NP_612153.2	Q6ISU1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTCRA	ENST00000304672.6 link	c.559C>T	p.Arg187Cys	missense_variant	Exon 4 of 4	1	NM_138296.3	ENSP00000304447.2	Q6ISU1-1
PTCRA	ENST00000441198.4 link	c.484C>T	p.Arg162Cys	missense_variant	Exon 5 of 5	1		ENSP00000409550.1	Q6ISU1-3
PTCRA	ENST00000446507.5 link	c.238C>T	p.Arg80Cys	missense_variant	Exon 3 of 3	1		ENSP00000392288.1	Q6ISU1-2
PTCRA	ENST00000616441.2 link	c.604C>T	p.Arg202Cys	missense_variant	Exon 4 of 4	2		ENSP00000477815.1	A0A087WTE9

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000341

AC:

AN:

155558

Hom.:

AF XY:

0.000349

AC XY:

AN XY:

83012

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000657

Gnomad NFE exome

AF:

0.000772

Gnomad OTH exome

AF:

0.000456

GnomAD4 exome

AF:

0.000579

AC:

812

AN:

1401714

Hom.:

Cov.:

AF XY:

0.000546

AC XY:

378

AN XY:

691910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000945

Gnomad4 AMR exome

AF:

0.000111

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000205

Gnomad4 NFE exome

AF:

0.000723

Gnomad4 OTH exome

AF:

0.000379

GnomAD4 genome

AF:

0.000400

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.000368

AC:

ExAC

AF:

0.000209

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.559C>T (p.R187C) alteration is located in exon 4 (coding exon 4) of the PTCRA gene. This alteration results from a C to T substitution at nucleotide position 559, causing the arginine (R) at amino acid position 187 to be replaced by a cysteine (C). 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

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.61

T;T;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;D;.

REVEL

Benign

0.054

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.12

MVP

0.64

MPC

0.57

ClinPred

0.071

GERP RS

0.33

Varity_R

0.22

gMVP

0.12

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over