1-198713049-C-T

Variant names:

• chr1-198713049-C-T
• rs6696162
• NM_002838.5:c.1268C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002838.5(PTPRC):​c.1268C>T​(p.Thr423Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,606 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -8.22
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033831298).
• BP6: Variant 1-198713049-C-T is Benign according to our data. Variant chr1-198713049-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00684 (1042/152242) while in subpopulation AFR AF = 0.0239 (994/41532). AF 95% confidence interval is 0.0227. There are 11 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1268C>T	p.Thr423Ile	missense	Exon 12 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.785C>T	p.Thr262Ile	missense	Exon 9 of 30	NP_563578.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.1268C>T	p.Thr423Ile	missense	Exon 12 of 33	ENSP00000411355.3
	PTPRC	ENST00000348564.12	TSL:1	c.785C>T	p.Thr262Ile	missense	Exon 9 of 30	ENSP00000306782.7
	PTPRC	ENST00000530727.5	TSL:1	c.926C>T	p.Thr309Ile	missense	Exon 10 of 18	ENSP00000433536.2

Frequencies

GnomAD3 genomes AF: 0.00684 AC: 1041 AN: 152124 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00168 AC: 421 AN: 251028 AF XY: 0.00125

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000693 AC: 1013 AN: 1461364 Hom.: 11 Cov.: 30 AF XY: 0.000620 AC XY: 451 AN XY: 726998

African (AFR) AF: 0.0244 AC: 816 AN: 33458

American (AMR) AF: 0.00127 AC: 57 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111640

Other (OTH) AF: 0.00161 AC: 97 AN: 60374

GnomAD4 genome AF: 0.00684 AC: 1042 AN: 152242 Hom.: 11 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74450

African (AFR) AF: 0.0239 AC: 994 AN: 41532

American (AMR) AF: 0.00183 AC: 28 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00246 Hom.: 15

Bravo AF: 0.00764

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 14, 2016

GeneDx

Significance: Likely 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.

Aug 19, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Immunodeficiency 104 Benign:1

Jan 29, 2025

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	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.0010
DANN	Benign	0.054
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
PhyloP100		-8.2
PrimateAI	Benign	0.31	T
REVEL	Benign	0.13
Sift4G	Benign	0.37	T
Vest4		0.080
MVP		0.36
MPC		0.19
ClinPred		0.0090	T
GERP RS		-8.4
Varity_R		0.067
gMVP		0.40
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6696162; hg19: chr1-198682178;