1-113833137-C-G

Variant names:

• chr1-113833137-C-G
• rs780303111
• ENST00000359785.10:c.2027G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000359785.10(PTPN22):​c.2027G>C​(p.Ser676Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTPN22 ENST00000359785.10 missense, splice_region
• Scores: Splicing: ADA: 0.0004048
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12659201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.2027G>C	p.Ser676Thr	missense_variant, splice_region_variant	Exon 16 of 21		NP_057051.4
PTPN22	NM_001308297.2	c.1955G>C	p.Ser652Thr	missense_variant, splice_region_variant	Exon 15 of 20		NP_001295226.2
PTPN22	NM_001193431.3	c.1943G>C	p.Ser648Thr	missense_variant, splice_region_variant	Exon 16 of 21		NP_001180360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.2027G>C	p.Ser676Thr	missense_variant, splice_region_variant	Exon 16 of 21	1		ENSP00000352833.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2027G>C (p.S676T) alteration is located in exon 16 (coding exon 16) of the PTPN22 gene. This alteration results from a G to C substitution at nucleotide position 2027, causing the serine (S) at amino acid position 676 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.11	.;.;T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.013
Sift	Uncertain	0.0050	D;.;D;D;D
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.11	.;.;.;B;.
Vest4		0.34
MutPred		0.19		Gain of sheet (P = 0.0266);.;.;Gain of sheet (P = 0.0266);.;
MVP		0.73
MPC		0.16
ClinPred		0.53	D
GERP RS		2.5
gMVP		0.16
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00040
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.020		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: rs780303111; hg19: chr1-114375759;