1-113829710-TAA-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_015967.8(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 NM_015967.8 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68

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

Our verdict: Likely_benign. The variant received -4 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.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0243 (25843/1063444) while in subpopulation SAS AF = 0.0462 (2775/60122). AF 95% confidence interval is 0.0447. There are 0 homozygotes in GnomAdExome4. There are 13188 alleles in the male GnomAdExome4 subpopulation. This position FAILED quality control check.

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

Gnomad4 AFR exome AF: 0.0334 AC: 733 AN: 21922

Gnomad4 AMR exome AF: 0.0141 AC: 396 AN: 28084

Gnomad4 ASJ exome AF: 0.0294 AC: 554 AN: 18832

Gnomad4 EAS exome AF: 0.00283 AC: 98 AN: 34568

Gnomad4 SAS exome AF: 0.0462 AC: 2775 AN: 60122

Gnomad4 FIN exome AF: 0.0167 AC: 678 AN: 40478

Gnomad4 NFE exome AF: 0.0240 AC: 19456 AN: 811034

Gnomad4 Remaining exome AF: 0.0237 AC: 1052 AN: 44454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), 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

Gnomad4 AFR AF: 0.000297 AC: 0.000297471 AN: 0.000297471

Gnomad4 AMR AF: 0.000750 AC: 0.000749523 AN: 0.000749523

Gnomad4 ASJ AF: 0.000583 AC: 0.000583431 AN: 0.000583431

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00186 AC: 0.00185955 AN: 0.00185955

Gnomad4 NFE AF: 0.000331 AC: 0.000330579 AN: 0.000330579

Gnomad4 OTH AF: 0.00146 AC: 0.00146484 AN: 0.00146484

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs57877024; hg19: chr1-114372332;