1-198638880-T-A

Variant names:

• chr1-198638880-T-A
• rs75725159
• ENST00000643513.1:c.-44+94T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000643513.1(PTPRC):​c.-44+94T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 205,828 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 32)
  • Exomes 𝑓: 0.011 (8 hom.)
• Consequence: PTPRC ENST00000643513.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.903
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-198638880-T-A is Benign according to our data. Variant chr1-198638880-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1201379.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.011 (1673/152256) while in subpopulation NFE AF = 0.0167 (1137/67976). AF 95% confidence interval is 0.0159. There are 20 homozygotes in GnomAd4. There are 772 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRC	NM_002838.5	c.-301T>A		upstream_gene_variant		ENST00000442510.8	NP_002829.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRC	ENST00000442510.8	c.-301T>A		upstream_gene_variant		1	NM_002838.5	ENSP00000411355.3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1672 AN: 152138 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0115 AC: 616 AN: 53572 Hom.: 8 Cov.: 0 AF XY: 0.0105 AC XY: 304 AN XY: 28846

African (AFR) AF: 0.00235 AC: 3 AN: 1274

American (AMR) AF: 0.00780 AC: 28 AN: 3588

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 61 AN: 1214

East Asian (EAS) AF: 0.00 AC: 0 AN: 2838

South Asian (SAS) AF: 0.00293 AC: 25 AN: 8534

European-Finnish (FIN) AF: 0.00326 AC: 6 AN: 1842

Middle Eastern (MID) AF: 0.0110 AC: 2 AN: 182

European-Non Finnish (NFE) AF: 0.0146 AC: 459 AN: 31338

Other (OTH) AF: 0.0116 AC: 32 AN: 2762

GnomAD4 genome AF: 0.0110 AC: 1673 AN: 152256 Hom.: 20 Cov.: 32 AF XY: 0.0104 AC XY: 772 AN XY: 74450

African (AFR) AF: 0.00286 AC: 119 AN: 41580

American (AMR) AF: 0.0107 AC: 164 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3472

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

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0167 AC: 1137 AN: 67976

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0150 Hom.: 5

Bravo AF: 0.0103

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 04, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.78
PhyloP100		0.90
PromoterAI		0.043	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs75725159; hg19: chr1-198608010;