1-113834471-A-G

Variant names:

• chr1-113834471-A-G
• rs1599971
• NM_015967.8:c.1895-32T>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.1895-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,592,586 control chromosomes in the GnomAD database, including 446,079 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.77 (45752 hom., cov: 33)
  • Exomes 𝑓: 0.74 (400327 hom.)
• Consequence: PTPN22 NM_015967.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545
• Publications: 22 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 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.1895-32T>C		intron	N/A	NP_057051.4
	PTPN22	NM_001308297.2		c.1823-32T>C		intron	N/A	NP_001295226.2
	PTPN22	NM_001193431.3		c.1895-32T>C		intron	N/A	NP_001180360.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN22	ENST00000359785.10	TSL:1 MANE Select	c.1895-32T>C		intron	N/A	ENSP00000352833.5
	PTPN22	ENST00000420377.6	TSL:1	c.1895-32T>C		intron	N/A	ENSP00000388229.2
	PTPN22	ENST00000538253.5	TSL:1	c.1823-32T>C		intron	N/A	ENSP00000439372.2

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116677 AN: 152040 Hom.: 45698 Cov.: 33

Gnomad AFR AF: 0.900

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.703 AC: 175823 AN: 250146 AF XY: 0.712

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.388

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.757

Gnomad OTH exome AF: 0.728

GnomAD4 exome AF: 0.741 AC: 1067643 AN: 1440428 Hom.: 400327 Cov.: 31 AF XY: 0.742 AC XY: 532848 AN XY: 717698

African (AFR) AF: 0.906 AC: 29833 AN: 32912

American (AMR) AF: 0.535 AC: 23823 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19524 AN: 25968

East Asian (EAS) AF: 0.394 AC: 15587 AN: 39532

South Asian (SAS) AF: 0.776 AC: 66438 AN: 85578

European-Finnish (FIN) AF: 0.689 AC: 36776 AN: 53364

Middle Eastern (MID) AF: 0.720 AC: 4117 AN: 5718

European-Non Finnish (NFE) AF: 0.757 AC: 827141 AN: 1093162

Other (OTH) AF: 0.744 AC: 44404 AN: 59684

GnomAD4 genome AF: 0.768 AC: 116792 AN: 152158 Hom.: 45752 Cov.: 33 AF XY: 0.761 AC XY: 56589 AN XY: 74366

African (AFR) AF: 0.900 AC: 37394 AN: 41528

American (AMR) AF: 0.641 AC: 9802 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2649 AN: 3470

East Asian (EAS) AF: 0.390 AC: 2019 AN: 5174

South Asian (SAS) AF: 0.770 AC: 3720 AN: 4832

European-Finnish (FIN) AF: 0.686 AC: 7240 AN: 10556

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.756 AC: 51435 AN: 67996

Other (OTH) AF: 0.744 AC: 1572 AN: 2112

Alfa AF: 0.756 Hom.: 21364

Bravo AF: 0.762

Asia WGS AF: 0.638 AC: 2219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.6
DANN	Benign	0.59
PhyloP100		0.55
BranchPoint Hunter		3.0
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1599971; hg19: chr1-114377093; COSMIC: COSV63084538;