rs145944629

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_002838.5(PTPRC):​c.2998G>A​(p.Asp1000Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000164 in 1,609,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1000E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PTPRC
NM_002838.5 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.94
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1542801).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/151838) while in subpopulation NFE AF= 0.00028 (19/67846). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPRCNM_002838.5 linkuse as main transcriptc.2998G>A p.Asp1000Asn missense_variant 28/33 ENST00000442510.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPRCENST00000442510.8 linkuse as main transcriptc.2998G>A p.Asp1000Asn missense_variant 28/331 NM_002838.5 A2P08575-3

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
151838
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.000280
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000192
AC:
48
AN:
249392
Hom.:
0
AF XY:
0.000178
AC XY:
24
AN XY:
134806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000204
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:
0.000347
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000165
AC:
241
AN:
1457232
Hom.:
0
Cov.:
31
AF XY:
0.000172
AC XY:
125
AN XY:
725156
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.000202
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:
0.000202
Gnomad4 OTH exome
AF:
0.0000832
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
151838
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74126
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000280
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000347
Hom.:
1
Bravo
AF:
0.000181
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000255
AC:
31
EpiCase
AF:
0.000382
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.2992G>A (p.D998N) alteration is located in exon 28 (coding exon 27) of the PTPRC gene. This alteration results from a G to A substitution at nucleotide position 2992, causing the aspartic acid (D) at amino acid position 998 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Immunodeficiency 104 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2022This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1000 of the PTPRC protein (p.Asp1000Asn). This variant is present in population databases (rs145944629, gnomAD 0.03%). 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: 533064). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.58
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
.;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-1.2
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Benign
0.24
Sift
Benign
0.057
T;D
Sift4G
Benign
0.16
T;T
Vest4
0.29
MVP
0.48
MPC
0.68
ClinPred
0.22
T
GERP RS
5.8
Varity_R
0.15
gMVP
0.49

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145944629; hg19: chr1-198718604; COSMIC: COSV61406021; COSMIC: COSV61406021; API