rs4915154

chr1-198702524-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002838.5(PTPRC):c.577A>G(p.Thr193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,614,082 control chromosomes in the GnomAD database, including 1,595 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T193T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (177 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1418 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.523464E-4).
• BP6: Variant 1-198702524-A-G is Benign according to our data. Variant chr1-198702524-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 464444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRC	NM_002838.5	c.577A>G	p.Thr193Ala	missense_variant	6/33	ENST00000442510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRC	ENST00000442510.8	c.577A>G	p.Thr193Ala	missense_variant	6/33	1	NM_002838.5	A2

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3117 AN: 152078 Hom.: 178 Cov.: 32

Gnomad AFR AF: 0.00536

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00784

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0430 AC: 10805 AN: 251468 Hom.: 722 AF XY: 0.0388 AC XY: 5279 AN XY: 135906

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.0459

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0185 AC: 26987 AN: 1461886 Hom.: 1418 Cov.: 32 AF XY: 0.0188 AC XY: 13696 AN XY: 727244

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.0446

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00730

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152196 Hom.: 177 Cov.: 32 AF XY: 0.0223 AC XY: 1658 AN XY: 74406

Gnomad4 AFR AF: 0.00535

Gnomad4 AMR AF: 0.0602

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.0496

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00782

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0177 Hom.: 312

Bravo AF: 0.0277

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.0393 AC: 4772

Asia WGS AF: 0.134 AC: 464 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 12716971, 16538473, 15333587) -

Immunodeficiency 105 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2023

- -

Immunodeficiency 104 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.0070
Dann	Benign	0.37
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.00085	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
REVEL	Benign	0.069
Sift4G	Benign	0.27	T;T
Vest4		0.0070
MPC		0.17
ClinPred		0.0043	T
GERP RS		-12
Varity_R		0.043
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs4915154; hg19: chr1-198671653; COSMIC: COSV61408432; COSMIC: COSV61408432;