rs1566734

Variant names:

• chr11-48123823-A-C
• rs1566734
• NM_002843.4:c.827A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-48123823-A-C
• chr11-48123823-A-G
• chr11-48123823-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002843.4(PTPRJ):​c.827A>C​(p.Gln276Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,772 control chromosomes in the GnomAD database, including 23,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (1847 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21299 hom.)
• Consequence: PTPRJ NM_002843.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 0.0800
• Publications: 64 publications found

Genes affected

PTPRJ (HGNC:9673): (protein tyrosine phosphatase receptor type J) 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, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region containing five fibronectin type III repeats, a single transmembrane region, and a single intracytoplasmic catalytic domain, and thus represents a receptor-type PTP. This protein is present in all hematopoietic lineages, and was shown to negatively regulate T cell receptor signaling possibly through interfering with the phosphorylation of Phospholipase C Gamma 1 and Linker for Activation of T Cells. This protein can also dephosphorylate the PDGF beta receptor, and may be involved in UV-induced signal transduction. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PTPRJ Gene-Disease associations (from GenCC):

• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• thrombocytopenia 10

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005792141).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRJ	NM_002843.4	c.827A>C	p.Gln276Pro	missense_variant	Exon 5 of 25	ENST00000418331.7	NP_002834.3
PTPRJ	NM_001098503.2	c.827A>C	p.Gln276Pro	missense_variant	Exon 5 of 9		NP_001091973.1
PTPRJ	XM_017018085.2	c.779A>C	p.Gln260Pro	missense_variant	Exon 5 of 25		XP_016873574.1
PTPRJ	XM_047427374.1	c.1169A>C	p.Gln390Pro	missense_variant	Exon 5 of 17		XP_047283330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRJ	ENST00000418331.7	c.827A>C	p.Gln276Pro	missense_variant	Exon 5 of 25	1	NM_002843.4	ENSP00000400010.2
PTPRJ	ENST00000440289.6	c.827A>C	p.Gln276Pro	missense_variant	Exon 5 of 9	1		ENSP00000409733.2
PTPRJ	ENST00000698881.1	c.1169A>C	p.Gln390Pro	missense_variant	Exon 5 of 25			ENSP00000514003.1
PTPRJ	ENST00000527952.1	c.*123A>C		downstream_gene_variant		5		ENSP00000435618.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23059 AN: 152020 Hom.: 1848 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.0990

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.169 AC: 42380 AN: 251292 AF XY: 0.179

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.165 AC: 241340 AN: 1461634 Hom.: 21299 Cov.: 35 AF XY: 0.169 AC XY: 122945 AN XY: 727154

African (AFR) AF: 0.116 AC: 3873 AN: 33472

American (AMR) AF: 0.101 AC: 4517 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6252 AN: 26130

East Asian (EAS) AF: 0.241 AC: 9580 AN: 39700

South Asian (SAS) AF: 0.267 AC: 23020 AN: 86252

European-Finnish (FIN) AF: 0.0997 AC: 5326 AN: 53410

Middle Eastern (MID) AF: 0.267 AC: 1540 AN: 5760

European-Non Finnish (NFE) AF: 0.158 AC: 176202 AN: 1111802

Other (OTH) AF: 0.183 AC: 11030 AN: 60384

GnomAD4 genome AF: 0.152 AC: 23056 AN: 152138 Hom.: 1847 Cov.: 32 AF XY: 0.152 AC XY: 11286 AN XY: 74380

African (AFR) AF: 0.119 AC: 4952 AN: 41506

American (AMR) AF: 0.148 AC: 2257 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1429 AN: 5152

South Asian (SAS) AF: 0.248 AC: 1193 AN: 4812

European-Finnish (FIN) AF: 0.0990 AC: 1049 AN: 10598

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10811 AN: 67984

Other (OTH) AF: 0.179 AC: 378 AN: 2114

Alfa AF: 0.169 Hom.: 6680

Bravo AF: 0.152

TwinsUK AF: 0.155 AC: 573

ALSPAC AF: 0.149 AC: 574

ESP6500AA AF: 0.120 AC: 528

ESP6500EA AF: 0.162 AC: 1389

ExAC AF: 0.169 AC: 20522

Asia WGS AF: 0.245 AC: 851 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 28, 2020

H3Africa Consortium

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.063, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Pathogenic:1

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Colorectal cancer Benign:1

Dec 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTPRJ-related disorder Benign:1

Oct 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.7
DANN	Benign	0.47
DEOGEN2	Benign	0.089	T;T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.36	T;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	.;L;.;L
PhyloP100		0.080
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.21	.;N;.;N
REVEL	Benign	0.014
Sift	Benign	0.24	.;T;.;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0010	.;B;.;.
Vest4		0.21
MPC		0.33
ClinPred		0.0040	T
GERP RS		1.5
Varity_R		0.087
gMVP		0.76
Mutation Taster		=93/7	disease causing (ClinVar)

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: rs1566734; hg19: chr11-48145375; COSMIC: COSV69249563; COSMIC: COSV69249563;