1-113834471-A-G

Variant names:

• chr1-113834471-A-G
• rs1599971
• ENST00000359785.10:c.1895-32T>C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.1895-32T>C		intron_variant	Intron 14 of 20		NP_057051.4
PTPN22	NM_001308297.2	c.1823-32T>C		intron_variant	Intron 13 of 19		NP_001295226.2
PTPN22	NM_001193431.3	c.1895-32T>C		intron_variant	Intron 14 of 20		NP_001180360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.1895-32T>C		intron_variant	Intron 14 of 20	1		ENSP00000352833.5

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

GnomAD3 exomes AF: 0.703 AC: 175823 AN: 250146 Hom.: 64072 AF XY: 0.712 AC XY: 96301 AN XY: 135284

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 SAS exome AF: 0.780

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

Gnomad4 AFR exome AF: 0.906

Gnomad4 AMR exome AF: 0.535

Gnomad4 ASJ exome AF: 0.752

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.689

Gnomad4 NFE exome AF: 0.757

Gnomad4 OTH exome AF: 0.744

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

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.763

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.770

Gnomad4 FIN AF: 0.686

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.744

Alfa AF: 0.759 Hom.: 12893

Bravo AF: 0.762

Asia WGS AF: 0.638 AC: 2219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.6
DANN	Benign	0.59
BranchPoint Hunter		3.0

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