1-113825156-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000359785.10(PTPN22):c.2267G>A(p.Arg756Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,506,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PTPN22 ENST00000359785.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896

Genes affected

PTPN22 (HGNC:9652): (protein tyrosine phosphatase non-receptor type 22) This gene encodes of member of the non-receptor class 4 subfamily of the protein-tyrosine phosphatase family. The encoded protein is a lymphoid-specific intracellular phosphatase that associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. Mutations in this gene may be associated with a range of autoimmune disorders including Type 1 Diabetes, rheumatoid arthritis, systemic lupus erythematosus and Graves' disease. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Mar 2009]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23031986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN22	NM_015967.8	c.2267G>A	p.Arg756Gln	missense_variant	19/21	ENST00000359785.10
PTPN22	XM_047417630.1	c.2117G>A	p.Arg706Gln	missense_variant	17/19
AP4B1-AS1	NR_125965.1	n.414+9684C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN22	ENST00000359785.10	c.2267G>A	p.Arg756Gln	missense_variant	19/21	1	NM_015967.8	P1
	ENST00000664434.1	n.419-6606C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000384 AC: 8 AN: 208250 Hom.: 0 AF XY: 0.0000444 AC XY: 5 AN XY: 112568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000736

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.0000266 AC: 36 AN: 1354542 Hom.: 0 Cov.: 26 AF XY: 0.0000282 AC XY: 19 AN XY: 674688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000803

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000778

Gnomad4 SAS exome AF: 0.0000261

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.0000203

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151890 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74186

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000332 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.2267G>A (p.R756Q) alteration is located in exon 19 (coding exon 19) of the PTPN22 gene. This alteration results from a G to A substitution at nucleotide position 2267, causing the arginine (R) at amino acid position 756 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.51	D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;.;D;D;D
Sift4G	Benign	0.12	T;T;T;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.37
MutPred		0.21		Loss of MoRF binding (P = 0.0562);.;.;Loss of MoRF binding (P = 0.0562);.;
MVP		0.80
MPC		0.18
ClinPred		0.29	T
GERP RS		4.1
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs757586436; hg19: chr1-114367778;