1-198694393-C-T

Variant names:

• chr1-198694393-C-T
• rs12134940
• ENST00000413409.6:c.*212C>T

Variant summary

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

The NM_002838.5(PTPRC):​c.100+2020C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,088,604 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 31)
  • Exomes 𝑓: 0.015 (148 hom.)
• Consequence: PTPRC NM_002838.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.305
• Publications: 0 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=-0.93).
• BP6: Variant 1-198694393-C-T is Benign according to our data. Variant chr1-198694393-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1197008.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1967/152208) while in subpopulation NFE AF = 0.0161 (1092/68002). AF 95% confidence interval is 0.0153. There are 22 homozygotes in GnomAd4. There are 1045 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPRC	NM_002838.5	c.100+2020C>T		intron_variant	Intron 3 of 32	ENST00000442510.8	NP_002829.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPRC	ENST00000442510.8	c.100+2020C>T		intron_variant	Intron 3 of 32	1	NM_002838.5	ENSP00000411355.3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1966 AN: 152090 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0145 AC: 13586 AN: 936396 Hom.: 148 Cov.: 12 AF XY: 0.0143 AC XY: 6476 AN XY: 451800

African (AFR) AF: 0.00185 AC: 36 AN: 19430

American (AMR) AF: 0.00767 AC: 71 AN: 9262

Ashkenazi Jewish (ASJ) AF: 0.00254 AC: 35 AN: 13792

East Asian (EAS) AF: 0.00 AC: 0 AN: 22002

South Asian (SAS) AF: 0.0117 AC: 382 AN: 32572

European-Finnish (FIN) AF: 0.0316 AC: 614 AN: 19406

Middle Eastern (MID) AF: 0.0104 AC: 28 AN: 2702

European-Non Finnish (NFE) AF: 0.0154 AC: 11947 AN: 778244

Other (OTH) AF: 0.0121 AC: 473 AN: 38986

GnomAD4 genome AF: 0.0129 AC: 1967 AN: 152208 Hom.: 22 Cov.: 31 AF XY: 0.0140 AC XY: 1045 AN XY: 74418

African (AFR) AF: 0.00229 AC: 95 AN: 41540

American (AMR) AF: 0.0103 AC: 158 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.0482 AC: 510 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1092 AN: 68002

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00726 Hom.: 0

Bravo AF: 0.00937

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 05, 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	-0.93
CADD	Benign	4.5
DANN	Benign	0.27
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

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: rs12134940; hg19: chr1-198663522;