chr1-113834946-A-G

Variant names:

• chr1-113834946-A-G
• rs2476601
• ENST00000359785.10:c.1858T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• 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

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5175065E-7).
• BP6: Variant 1-113834946-A-G is Benign according to our data. Variant chr1-113834946-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.1858T>C	p.Trp620Arg	missense_variant	Exon 14 of 21	1		ENSP00000352833.5

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

Gnomad4 AFR exome AF: 0.987 AC: 30184 AN: 30578

Gnomad4 AMR exome AF: 0.967 AC: 35158 AN: 36342

Gnomad4 ASJ exome AF: 0.952 AC: 24072 AN: 25296

Gnomad4 EAS exome AF: 1.00 AC: 36601 AN: 36604

Gnomad4 SAS exome AF: 0.985 AC: 79273 AN: 80446

Gnomad4 FIN exome AF: 0.855 AC: 45465 AN: 53150

Gnomad4 NFE exome AF: 0.899 AC: 985502 AN: 1095922

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.985 AC: 0.984833 AN: 0.984833

Gnomad4 AMR AF: 0.961 AC: 0.960974 AN: 0.960974

Gnomad4 ASJ AF: 0.944 AC: 0.944124 AN: 0.944124

Gnomad4 EAS AF: 1.00 AC: 0.999614 AN: 0.999614

Gnomad4 SAS AF: 0.987 AC: 0.987355 AN: 0.987355

Gnomad4 FIN AF: 0.853 AC: 0.853391 AN: 0.853391

Gnomad4 NFE AF: 0.900 AC: 0.899577 AN: 0.899577

Gnomad4 OTH AF: 0.946 AC: 0.946074 AN: 0.946074

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 v4.3

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;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.025	T;T;T;T;T
MetaRNN	Benign	5.5e-7	T;T;T;T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	5.1	N;.;N;N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.13
MutPred		0.37		Gain of disorder (P = 6e-04);.;.;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

Publications

LitVar

Other links and lift over

dbSNP: rs2476601; hg19: chr1-114377568; COSMIC: COSV107454001;