1-113858609-A-T

Variant names:

• chr1-113858609-A-T
• rs1217418
• NM_015967.8:c.274-36T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015967.8(PTPN22):​c.274-36T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000088 in 1,135,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: PTPN22 NM_015967.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.274-36T>A		intron_variant	Intron 3 of 20	ENST00000359785.10	NP_057051.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.274-36T>A		intron_variant	Intron 3 of 20	1	NM_015967.8	ENSP00000352833.5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 8.80e-7 AC: 1 AN: 1135798 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 571002

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25260

American (AMR) AF: 0.00 AC: 0 AN: 28146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21854

East Asian (EAS) AF: 0.00 AC: 0 AN: 36250

South Asian (SAS) AF: 0.00 AC: 0 AN: 70426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3518

European-Non Finnish (NFE) AF: 0.00000117 AC: 1 AN: 852054

Other (OTH) AF: 0.00 AC: 0 AN: 48922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.50
DANN	Benign	0.67
PhyloP100		-0.10

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: rs1217418; hg19: chr1-114401231;