dbSNP rs57877024: PTPN22:c.2135-7_2135-4delTTTT (chr1-113829710-TAAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015967.8(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
NM_015967.8 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

0 publications found

Variant links:

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]

PTPN22 links:

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

AP4B1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015967.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PTPN22	NM_015967.8	MANE Select	c.2135-7_2135-4delTTTT	splice_region intron	N/A	NP_057051.4
PTPN22	NM_001308297.2		c.2063-7_2063-4delTTTT	splice_region intron	N/A	NP_001295226.2	F5H2S8
PTPN22	NM_001193431.3		c.2051-7_2051-4delTTTT	splice_region intron	N/A	NP_001180360.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PTPN22	ENST00000359785.10	TSL:1 MANE Select	c.2135-7_2135-4delTTTT	splice_region intron	N/A	ENSP00000352833.5	A0A0B4J1S7
PTPN22	ENST00000420377.6	TSL:1	c.2135-7_2135-4delTTTT	splice_region intron	N/A	ENSP00000388229.2	E9PMT0
PTPN22	ENST00000538253.5	TSL:1	c.2063-7_2063-4delTTTT	splice_region intron	N/A	ENSP00000439372.2	F5H2S8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147122

Hom.:

Cov.:

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:

AN:

1120886

Hom.:

AF XY:

0.00

AC XY:

AN XY:

564850

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23638

American (AMR)

AF:

0.00

AC:

AN:

29468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20244

East Asian (EAS)

AF:

0.00

AC:

AN:

35062

South Asian (SAS)

AF:

0.00

AC:

AN:

65928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.00000117

AC:

AN:

852530

Other (OTH)

AF:

0.00

AC:

AN:

47210

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71470

African (AFR)

AF:

0.00

AC:

AN:

40270

American (AMR)

AF:

0.00

AC:

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.00

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66634

Other (OTH)

AF:

0.00

AC:

AN:

2030

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over