Genetic Variant ENST00000359785.10:c.2272A>T (chr1-113825151-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000359785.10(PTPN22):c.2272A>T(p.Met758Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M758V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

PTPN22
ENST00000359785.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.581

Publications

0 publications found

Variant links:

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]

PTPN22 links:

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

AP4B1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13864794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359785.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN22	NM_015967.8	MANE Select	c.2272A>T	p.Met758Leu	missense	Exon 19 of 21	NP_057051.4
PTPN22	NM_001308297.2		c.2200A>T	p.Met734Leu	missense	Exon 18 of 20	NP_001295226.2	F5H2S8
PTPN22	NM_001193431.3		c.2188A>T	p.Met730Leu	missense	Exon 19 of 21	NP_001180360.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN22	ENST00000359785.10	TSL:1 MANE Select	c.2272A>T	p.Met758Leu	missense	Exon 19 of 21	ENSP00000352833.5	A0A0B4J1S7
PTPN22	ENST00000420377.6	TSL:1	c.2272A>T	p.Met758Leu	missense	Exon 19 of 20	ENSP00000388229.2	E9PMT0
PTPN22	ENST00000538253.5	TSL:1	c.2200A>T	p.Met734Leu	missense	Exon 18 of 20	ENSP00000439372.2	F5H2S8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000481

AC:

AN:

207744

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.031

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.84

M_CAP

Benign

0.0089

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

PhyloP100

-0.58

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

REVEL

Benign

0.069

Sift

Benign

0.13

Sift4G

Benign

0.57

Polyphen

0.046

Vest4

0.41

MutPred

0.24

Gain of methylation at K759 (P = 0.0657)

MVP

0.53

MPC

0.085

ClinPred

0.48

GERP RS

-0.12

gMVP

0.11

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over