rs12136658

Positions:

chr1-198722466-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002838.5(PTPRC):c.1710T>A(p.His570Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,463,760 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H570Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.015 ( 219 hom. )

Consequence

PTPRC
NM_002838.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.38

Variant links:

Genes affected

PTPRC (HGNC:9666): (protein tyrosine phosphatase receptor type C) 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, mitosis, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus is classified as a receptor type PTP. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jun 2012]

PTPRC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003068).

BP6

Variant 1-198722466-T-A is Benign according to our data. Variant chr1-198722466-T-A is described in ClinVar as [Benign]. Clinvar id is 138850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-198722466-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (1973/149764) while in subpopulation NFE AF= 0.0159 (1068/67344). AF 95% confidence interval is 0.0151. There are 24 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRC	NM_002838.5 linkuse as main transcript	c.1710T>A	p.His570Gln	missense_variant	15/33	ENST00000442510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRC	ENST00000442510.8 linkuse as main transcript	c.1710T>A	p.His570Gln	missense_variant	15/33	1	NM_002838.5	A2	P08575-3

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

1974

AN:

149736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00433

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0121

Gnomad FIN

AF:

0.0478

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0131

GnomAD3 exomes

AF:

0.0145

AC:

3100

AN:

214020

Hom.:

AF XY:

0.0150

AC XY:

1759

AN XY:

117204

show subpopulations

Gnomad AFR exome

AF:

0.00389

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.00521

Gnomad EAS exome

AF:

0.000212

Gnomad SAS exome

AF:

0.0120

Gnomad FIN exome

AF:

0.0484

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0152

AC:

20026

AN:

1313996

Hom.:

219

Cov.:

AF XY:

0.0152

AC XY:

9898

AN XY:

650040

show subpopulations

Gnomad4 AFR exome

AF:

0.00425

Gnomad4 AMR exome

AF:

0.00682

Gnomad4 ASJ exome

AF:

0.00389

Gnomad4 EAS exome

AF:

0.0000294

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.0453

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0132

AC:

1973

AN:

149764

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1048

AN XY:

73068

show subpopulations

Gnomad4 AFR

AF:

0.00430

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.0121

Gnomad4 FIN

AF:

0.0478

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.0130

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00994

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0173

AC:

148

ExAC

AF:

0.0135

AC:

1637

Asia WGS

AF:

0.00503

AC:

AN:

3394

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Immunodeficiency 104

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.0010

DANN

Benign

0.54

DEOGEN2

Benign

0.0091

.;.;T;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.040

T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.31

REVEL

Benign

0.055

Sift4G

Benign

0.33

T;T;T;T

Vest4

0.022

MPC

0.17

ClinPred

0.0021

GERP RS

-8.2

Varity_R

0.038

gMVP

0.60

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