1-113829710-TAA-T

Variant names:

• chr1-113829710-TAA-T
• rs57877024
• ENST00000359785.10:c.2135-5_2135-4delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000359785.10(PTPN22):​c.2135-5_2135-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,210,494 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.024 (0 hom.)
• Consequence: PTPN22 ENST00000359785.10 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68
• Publications: 4 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 0 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0447) population. However there is too low homozygotes in high coverage region: (expected more than 138, got 0).
• BP6: Variant 1-113829710-TAA-T is Benign according to our data. Variant chr1-113829710-TAA-T is described in ClinVar as [Benign]. Clinvar id is 775137.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.2135-5_2135-4delTT		splice_region_variant, intron_variant	Intron 17 of 20		NP_057051.4
PTPN22	NM_001308297.2	c.2063-5_2063-4delTT		splice_region_variant, intron_variant	Intron 16 of 19		NP_001295226.2
PTPN22	NM_001193431.3	c.2051-5_2051-4delTT		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.2135-5_2135-4delTT		splice_region_variant, intron_variant	Intron 17 of 20	1		ENSP00000352833.5

Frequencies

GnomAD3 genomes AF: 0.000456 AC: 67 AN: 146968 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000750

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00186

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000331

Gnomad OTH AF: 0.00148

GnomAD2 exomes AF: 0.0297 AC: 4452 AN: 149926 AF XY: 0.0314

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.00520

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0375

GnomAD4 exome AF: 0.0243 AC: 25843 AN: 1063444 Hom.: 0 AF XY: 0.0247 AC XY: 13188 AN XY: 533856

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

African (AFR) AF: 0.0334 AC: 733 AN: 21922

American (AMR) AF: 0.0141 AC: 396 AN: 28084

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 554 AN: 18832

East Asian (EAS) AF: 0.00283 AC: 98 AN: 34568

South Asian (SAS) AF: 0.0462 AC: 2775 AN: 60122

European-Finnish (FIN) AF: 0.0167 AC: 678 AN: 40478

Middle Eastern (MID) AF: 0.0256 AC: 101 AN: 3950

European-Non Finnish (NFE) AF: 0.0240 AC: 19456 AN: 811034

Other (OTH) AF: 0.0237 AC: 1052 AN: 44454

⚠️ 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 AF: 0.000456 AC: 67 AN: 147050 Hom.: 0 Cov.: 0 AF XY: 0.000434 AC XY: 31 AN XY: 71478

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

African (AFR) AF: 0.000297 AC: 12 AN: 40340

American (AMR) AF: 0.000750 AC: 11 AN: 14676

Ashkenazi Jewish (ASJ) AF: 0.000583 AC: 2 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00 AC: 0 AN: 4668

European-Finnish (FIN) AF: 0.00186 AC: 17 AN: 9142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000331 AC: 22 AN: 66550

Other (OTH) AF: 0.00146 AC: 3 AN: 2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 684

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism

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;