NM_002838.5:c.2543C>T

Variant names:

• chr1-198742008-C-T
• rs765136427
• NM_002838.5:c.2543C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002838.5(PTPRC):​c.2543C>T​(p.Pro848Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,611,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.82
• Publications: 1 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]

MIR181A1HG (HGNC:48659): (MIR181A1 host gene)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	NM_002838.5	MANE Select	c.2543C>T	p.Pro848Leu	missense	Exon 24 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.2060C>T	p.Pro687Leu	missense	Exon 21 of 30	NP_563578.2	P08575-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.2543C>T	p.Pro848Leu	missense	Exon 24 of 33	ENSP00000411355.3	P08575-3
	PTPRC	ENST00000348564.12	TSL:1	c.2060C>T	p.Pro687Leu	missense	Exon 21 of 30	ENSP00000306782.7	P08575-4
	PTPRC	ENST00000697631.1		c.2258C>T	p.Pro753Leu	missense	Exon 22 of 31	ENSP00000513363.1	P08575-8

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 249650 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460016 Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23 AN XY: 726358

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.0000449 AC: 2 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111032

Other (OTH) AF: 0.0000830 AC: 5 AN: 60258

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151196 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73810

African (AFR) AF: 0.00 AC: 0 AN: 41186

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67742

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.0000565 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 104 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.60	T
PhyloP100		7.8
PrimateAI	Pathogenic	0.79	T
REVEL	Uncertain	0.54
Sift4G	Uncertain	0.0020	D
Vest4		0.94
MVP		0.89
MPC		0.71
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.84
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs765136427; hg19: chr1-198711137; COSMIC: COSV61418526;