NM_002838.5:c.1710T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/19 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:5

Conservation

PhyloP100: -4.38

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 104
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
T-B+ severe combined immunodeficiency due to CD45 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PTPRC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 138850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002838.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	NM_002838.5	MANE Select	c.1710T>A	p.His570Gln	missense	Exon 15 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.1227T>A	p.His409Gln	missense	Exon 12 of 30	NP_563578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.1710T>A	p.His570Gln	missense	Exon 15 of 33	ENSP00000411355.3
PTPRC	ENST00000348564.12	TSL:1	c.1227T>A	p.His409Gln	missense	Exon 12 of 30	ENSP00000306782.7
PTPRC	ENST00000530727.5	TSL:1	c.1368T>A	p.His456Gln	missense	Exon 13 of 18	ENSP00000433536.2

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

GnomAD2 exomes

AF:

0.0145

AC:

3100

AN:

214020

AF XY:

0.0150

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 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

African (AFR)

AF:

0.00425

AC:

124

AN:

29168

American (AMR)

AF:

0.00682

AC:

248

AN:

36386

Ashkenazi Jewish (ASJ)

AF:

0.00389

AC:

AN:

22364

East Asian (EAS)

AF:

0.0000294

AC:

AN:

34004

South Asian (SAS)

AF:

0.0115

AC:

686

AN:

59722

European-Finnish (FIN)

AF:

0.0453

AC:

1950

AN:

43062

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

4756

European-Non Finnish (NFE)

AF:

0.0157

AC:

16166

AN:

1031636

Other (OTH)

AF:

0.0133

AC:

706

AN:

52898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0132

AC:

1973

AN:

149764

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1048

AN XY:

73068

show subpopulations

African (AFR)

AF:

0.00430

AC:

177

AN:

41174

American (AMR)

AF:

0.0106

AC:

159

AN:

15014

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5154

South Asian (SAS)

AF:

0.0121

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.0478

AC:

457

AN:

9558

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0159

AC:

1068

AN:

67344

Other (OTH)

AF:

0.0130

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 02, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Immunodeficiency 104

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.0010

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0091

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.040

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.92

PhyloP100

-4.4

PrimateAI

Benign

0.31

REVEL

Benign

0.055

Sift4G

Benign

0.33

Vest4

0.022

MPC

0.17

ClinPred

0.0021

GERP RS

-8.2

Varity_R

0.038

gMVP

0.60

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over