rs61749266

chr1-198716831-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002838.5(PTPRC):c.1441A>G(p.Lys481Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,584 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K481R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.18

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004903972).
• BP6: Variant 1-198716831-A-G is Benign according to our data. Variant chr1-198716831-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575499.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000709 (108/152374) while in subpopulation NFE AF= 0.00144 (98/68034). AF 95% confidence interval is 0.00121. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPRC	NM_002838.5	c.1441A>G	p.Lys481Glu	missense_variant	13/33	ENST00000442510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPRC	ENST00000442510.8	c.1441A>G	p.Lys481Glu	missense_variant	13/33	1	NM_002838.5	A2

Frequencies

GnomAD3 genomes AF: 0.000709 AC: 108 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00144

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000777 AC: 195 AN: 251058 Hom.: 0 AF XY: 0.000847 AC XY: 115 AN XY: 135700

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00157 AC: 2300 AN: 1461210 Hom.: 5 Cov.: 31 AF XY: 0.00153 AC XY: 1114 AN XY: 726918

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74516

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000812

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 104 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2022

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 481 of the PTPRC protein (p.Lys481Glu). This variant is present in population databases (rs61749266, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PTPRC-related conditions. ClinVar contains an entry for this variant (Variation ID: 575499). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.0040
Dann	Benign	0.36
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.30	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
REVEL	Benign	0.034
Sift4G	Benign	0.62	T;T;T;T
Vest4		0.052
MVP		0.24
MPC		0.24
ClinPred		0.0034	T
GERP RS		-5.7
Varity_R		0.15
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749266; hg19: chr1-198685960; COSMIC: COSV105265118;