ENST00000359785.10:c.2135-7_2135-4delTTTT

Variant names:

• chr1-113829710-TAAAA-T
• rs57877024
• ENST00000359785.10:c.2135-7_2135-4delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000359785.10(PTPN22):​c.2135-7_2135-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000892 in 1,120,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN22 ENST00000359785.10 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.2135-7_2135-4delTTTT		splice_region_variant, intron_variant	Intron 17 of 20		NP_057051.4
PTPN22	NM_001308297.2	c.2063-7_2063-4delTTTT		splice_region_variant, intron_variant	Intron 16 of 19		NP_001295226.2
PTPN22	NM_001193431.3	c.2051-7_2051-4delTTTT		splice_region_variant, intron_variant	Intron 17 of 20		NP_001180360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.2135-7_2135-4delTTTT		splice_region_variant, intron_variant	Intron 17 of 20	1		ENSP00000352833.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147122 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.92e-7 AC: 1 AN: 1120886 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 564850

⚠️ 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: 23638

American (AMR) AF: 0.00 AC: 0 AN: 29468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20244

East Asian (EAS) AF: 0.00 AC: 0 AN: 35062

South Asian (SAS) AF: 0.00 AC: 0 AN: 65928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4150

European-Non Finnish (NFE) AF: 0.00000117 AC: 1 AN: 852530

Other (OTH) AF: 0.00 AC: 0 AN: 47210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147122 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71470

African (AFR) AF: 0.00 AC: 0 AN: 40270

American (AMR) AF: 0.00 AC: 0 AN: 14664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66634

Other (OTH) AF: 0.00 AC: 0 AN: 2030

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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: rs57877024; hg19: chr1-114372332;