rs114970039

Variant names:

• chr1-198754304-T-C
• rs114970039
• NM_002838.5:c.3545T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BS1_Supporting

The NM_002838.5(PTPRC):​c.3545T>C​(p.Leu1182Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,611,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1182L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: PTPRC NM_002838.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 7.27
• Publications: 3 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]

MIR181A1HG (HGNC:48659): (MIR181A1 host gene)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000276 (42/152174) while in subpopulation NFE AF = 0.0005 (34/67960). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 20 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.3545T>C	p.Leu1182Ser	missense	Exon 32 of 33	NP_002829.3
	PTPRC	NM_080921.4		c.3062T>C	p.Leu1021Ser	missense	Exon 29 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.3545T>C	p.Leu1182Ser	missense	Exon 32 of 33	ENSP00000411355.3	P08575-3
	PTPRC	ENST00000348564.12	TSL:1	c.3062T>C	p.Leu1021Ser	missense	Exon 29 of 30	ENSP00000306782.7	P08575-4
	PTPRC	ENST00000697631.1		c.3260T>C	p.Leu1087Ser	missense	Exon 30 of 31	ENSP00000513363.1	P08575-8

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000248 AC: 62 AN: 250448 AF XY: 0.000310

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000568 AC: 829 AN: 1459756 Hom.: 1 Cov.: 31 AF XY: 0.000549 AC XY: 399 AN XY: 726306

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.000224 AC: 10 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53352

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.000693 AC: 770 AN: 1110370

Other (OTH) AF: 0.000547 AC: 33 AN: 60300

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74388

African (AFR) AF: 0.0000481 AC: 2 AN: 41578

American (AMR) AF: 0.000262 AC: 4 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67960

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000290 Hom.: 1

Bravo AF: 0.000314

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Immunodeficiency 104 (3)
1	1	-	not provided (2)
-	1	-	Hepatitis C virus, susceptibility to;C5676890:Immunodeficiency 104 (1)
-	1	-	Immunodeficiency 105 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.71	D
PhyloP100		7.3
PrimateAI	Uncertain	0.51	T
REVEL	Pathogenic	0.85
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MVP		0.90
MPC		0.82
ClinPred		0.86	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.72
Mutation Taster		=4/96	disease causing

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: rs114970039; hg19: chr1-198723433;