1-113834946-A-G

Variant names:

• chr1-113834946-A-G
• rs2476601
• NM_015967.8:c.1858T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015967.8(PTPN22):​c.1858T>C​(p.Trp620Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,574,936 control chromosomes in the GnomAD database, including 658,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W620G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.93 (66570 hom., cov: 31)
  • Exomes 𝑓: 0.91 (591587 hom.)
• Consequence: PTPN22 NM_015967.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.807
• Publications: 1593 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5175065E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015967.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN22	NM_015967.8	MANE Select	c.1858T>C	p.Trp620Arg	missense	Exon 14 of 21	NP_057051.4
	PTPN22	NM_001308297.2		c.1786T>C	p.Trp596Arg	missense	Exon 13 of 20	NP_001295226.2
	PTPN22	NM_001193431.3		c.1858T>C	p.Trp620Arg	missense	Exon 14 of 21	NP_001180360.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN22	ENST00000359785.10	TSL:1 MANE Select	c.1858T>C	p.Trp620Arg	missense	Exon 14 of 21	ENSP00000352833.5
	PTPN22	ENST00000420377.6	TSL:1	c.1858T>C	p.Trp620Arg	missense	Exon 14 of 20	ENSP00000388229.2
	PTPN22	ENST00000538253.5	TSL:1	c.1786T>C	p.Trp596Arg	missense	Exon 13 of 20	ENSP00000439372.2

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142065 AN: 152082 Hom.: 66511 Cov.: 31

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.961

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.944

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.988

Gnomad FIN AF: 0.853

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.900

Gnomad OTH AF: 0.946

GnomAD2 exomes AF: 0.929 AC: 203641 AN: 219224 AF XY: 0.930

Gnomad AFR exome AF: 0.986

Gnomad AMR exome AF: 0.969

Gnomad ASJ exome AF: 0.949

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.851

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.928

GnomAD4 exome AF: 0.911 AC: 1296378 AN: 1422736 Hom.: 591587 Cov.: 40 AF XY: 0.913 AC XY: 646370 AN XY: 707954

African (AFR) AF: 0.987 AC: 30184 AN: 30578

American (AMR) AF: 0.967 AC: 35158 AN: 36342

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 24072 AN: 25296

East Asian (EAS) AF: 1.00 AC: 36601 AN: 36604

South Asian (SAS) AF: 0.985 AC: 79273 AN: 80446

European-Finnish (FIN) AF: 0.855 AC: 45465 AN: 53150

Middle Eastern (MID) AF: 0.988 AC: 5625 AN: 5696

European-Non Finnish (NFE) AF: 0.899 AC: 985502 AN: 1095922

Other (OTH) AF: 0.928 AC: 54498 AN: 58702

GnomAD4 genome AF: 0.934 AC: 142183 AN: 152200 Hom.: 66570 Cov.: 31 AF XY: 0.935 AC XY: 69589 AN XY: 74402

African (AFR) AF: 0.985 AC: 40908 AN: 41538

American (AMR) AF: 0.961 AC: 14676 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 3278 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5176

South Asian (SAS) AF: 0.987 AC: 4763 AN: 4824

European-Finnish (FIN) AF: 0.853 AC: 9034 AN: 10586

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.900 AC: 61182 AN: 68012

Other (OTH) AF: 0.946 AC: 2000 AN: 2114

Alfa AF: 0.916 Hom.: 281786

Bravo AF: 0.944

TwinsUK AF: 0.897 AC: 3327

ALSPAC AF: 0.899 AC: 3465

ESP6500AA AF: 0.982 AC: 4326

ESP6500EA AF: 0.906 AC: 7791

ExAC AF: 0.933 AC: 113294

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.020
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.025	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.81
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	5.1	N
REVEL	Benign	0.063
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.37		Gain of disorder (P = 6e-04)
MPC		0.13
ClinPred		0.0017	T
GERP RS		2.7
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs2476601; hg19: chr1-114377568; COSMIC: COSV107454001;