rs140403368

Variant names:

• chr1-198716687-G-A
• rs140403368
• NM_002838.5:c.1297G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002838.5(PTPRC):​c.1297G>A​(p.Asp433Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,611,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:1
• Conservation: PhyloP100: -1.67
• Publications: 8 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009666443).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000986 (150/152108) while in subpopulation NFE AF = 0.0016 (109/68008). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002838.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	NM_002838.5	MANE Select	c.1297G>A	p.Asp433Asn	missense	Exon 13 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.814G>A	p.Asp272Asn	missense	Exon 10 of 30	NP_563578.2	P08575-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPRC	ENST00000442510.8	TSL:1 MANE Select	c.1297G>A	p.Asp433Asn	missense	Exon 13 of 33	ENSP00000411355.3	P08575-3
	PTPRC	ENST00000348564.12	TSL:1	c.814G>A	p.Asp272Asn	missense	Exon 10 of 30	ENSP00000306782.7	P08575-4
	PTPRC	ENST00000530727.5	TSL:1	c.955G>A	p.Asp319Asn	missense	Exon 11 of 18	ENSP00000433536.2	E9PKH0

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000891 AC: 223 AN: 250260 AF XY: 0.000856

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1459212 Hom.: 0 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 725940

African (AFR) AF: 0.0000299 AC: 1 AN: 33392

American (AMR) AF: 0.000671 AC: 30 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86116

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53408

Middle Eastern (MID) AF: 0.000472 AC: 2 AN: 4238

European-Non Finnish (NFE) AF: 0.00129 AC: 1430 AN: 1111476

Other (OTH) AF: 0.000897 AC: 54 AN: 60184

GnomAD4 genome AF: 0.000986 AC: 150 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.000969 AC XY: 72 AN XY: 74296

African (AFR) AF: 0.000435 AC: 18 AN: 41422

American (AMR) AF: 0.000720 AC: 11 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68008

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.00131 Hom.: 1

Bravo AF: 0.000903

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000906 AC: 110

EpiCase AF: 0.00115

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Immunodeficiency 104 (1)
-	-	1	PTPRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0010
DANN	Benign	0.68
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.7
PrimateAI	Benign	0.32	T
REVEL	Benign	0.044
Sift4G	Benign	0.65	T
Vest4		0.11
MVP		0.15
MPC		0.16
ClinPred		0.00096	T
GERP RS		-5.7
Varity_R		0.065
gMVP		0.30
Mutation Taster		=96/4	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: rs140403368; hg19: chr1-198685816; COSMIC: COSV100721967;