chr1-113825151-T-A

Variant names:

• chr1-113825151-T-A
• rs369890270
• ENST00000359785.10:c.2272A>T

Variant summary

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

The NM_015967.8(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. 14/19 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 NM_015967.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.581

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]

ENSG00000231128 (HGNC:):

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

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=0.13864794).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.2272A>T	p.Met758Leu	missense_variant	Exon 19 of 21	1		ENSP00000352833.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000481 AC: 1 AN: 207744 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112298

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 SAS 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.: 26

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.031	.;.;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.84	T;D;D;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N;.;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.13	T;.;T;D;D
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.046	.;.;.;B;.
Vest4		0.41
MutPred		0.24		Gain of methylation at K759 (P = 0.0657);.;.;Gain of methylation at K759 (P = 0.0657);.;
MVP		0.53
MPC		0.085
ClinPred		0.48	T
GERP RS		-0.12
gMVP		0.11

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

Other links and lift over

dbSNP: rs369890270; hg19: chr1-114367773;