rs150672767

Positions:

chr1-198755930-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002838.5(PTPRC):c.3670G>A(p.Val1224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,611,676 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1224V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 9 hom. )

Consequence

PTPRC
NM_002838.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.0820

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:

PTPRC (HGNC:):

PTPRC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004925579).

BP6

Variant 1-198755930-G-A is Benign according to our data. Variant chr1-198755930-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440224.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=2}. Variant chr1-198755930-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0015 (228/151960) while in subpopulation AMR AF= 0.00164 (25/15258). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPRC	NM_002838.5 linkuse as main transcript	c.3670G>A	p.Val1224Ile	missense_variant	33/33	ENST00000442510.8	NP_002829.3	P08575-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPRC	ENST00000442510.8 linkuse as main transcript	c.3670G>A	p.Val1224Ile	missense_variant	33/33	1	NM_002838.5	ENSP00000411355.3		P08575-3

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00194

AC:

485

AN:

250252

Hom.:

AF XY:

0.00208

AC XY:

282

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00149

AC:

2176

AN:

1459716

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1106

AN XY:

726312

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.00175

Gnomad4 ASJ exome

AF:

0.0207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00150

AC:

228

AN:

151960

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00176

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2017	The V1222I variant in the PTPRC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1222I variant is observed in 164/66528 (0.247%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals are reported to be homozygous (Lek et al., 2016). The V1222I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret V1222I as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 23, 2017	The p.Val1224Ile variant has not been reported in the scientific medical literature or gene specific variant databases. This variant (rs150672767) is listed in the Exome Aggregation Consortium with an overall allele frequency of 0.16 percent. Valine at codon 1224 is weakly conserved considering 10 species (Alamut software v2.7.1), and Orangutan, Rhesus, Baboon, Mouse and Xenopus tropicalis all have isoleucine, suggesting that this amino acid change may be evolutionary tolerated. Additionally, computational analyses do not agree in their assessment of the impact on the protein (PolyPhen2: benign, SIFT: tolerated, and Mutation Taster: disease causing). Thus, even though the conservation and computational data suggest that this variant may represent a benign polymorphism, the clinical significance of p.Val1224Ile variant cannot be determined with certainty. Pathogenic variants in PTPRC are causative for severe combined immunodeficiency (MIM: 608971), and are inherited in autosomal recessive manner. Thus, even if p.Val1224Ile was subsequently determined to be pathogenic, based on the available information, this patient would be a carrier, and may be affected if a second pathogenic PTPRC variant is present on the opposite chromosome but could not be detected by this assay (eg, deep intronic variants, or regulatory region variants). -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 12, 2022

- -

PTPRC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 104

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.0030

DANN

Benign

0.26

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.58

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.82

PrimateAI

Benign

0.25

REVEL

Uncertain

0.35

Sift4G

Benign

0.55

T;T

Vest4

0.097

MVP

0.25

MPC

0.14

ClinPred

0.0021

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.11

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