1-113830008-G-C

Position:

• chr1-113830008-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000359785.10(PTPN22):​c.2075C>G​(p.Ser692Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,605,180 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (49 hom.)
• Consequence: PTPN22 ENST00000359785.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.46

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045930743).
• BP6: Variant 1-113830008-G-C is Benign according to our data. Variant chr1-113830008-G-C is described in ClinVar as [Benign]. Clinvar id is 773112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00228 (347/152246) while in subpopulation AMR AF= 0.0194 (297/15302). AF 95% confidence interval is 0.0176. There are 12 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN22	NM_015967.8	c.2075C>G	p.Ser692Cys	missense_variant	17/21	ENST00000359785.10	NP_057051.4
PTPN22	XM_047417630.1	c.1925C>G	p.Ser642Cys	missense_variant	15/19		XP_047273586.1
AP4B1-AS1	NR_125965.1	n.414+14536G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN22	ENST00000359785.10	c.2075C>G	p.Ser692Cys	missense_variant	17/21	1	NM_015967.8	ENSP00000352833	P1
	ENST00000664434.1	n.419-1754G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152128 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00572 AC: 1433 AN: 250528 Hom.: 31 AF XY: 0.00433 AC XY: 586 AN XY: 135468

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00191

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00147 AC: 2141 AN: 1452934 Hom.: 49 Cov.: 30 AF XY: 0.00133 AC XY: 962 AN XY: 723326

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00215

Gnomad4 SAS exome AF: 0.000849

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000951

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152246 Hom.: 12 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74444

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.00393

ExAC AF: 0.00422 AC: 512

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	.;.;T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.96	D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D;.;D;D;N
REVEL	Benign	0.17
Sift	Benign	0.030	D;.;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.27
MVP		0.74
MPC		0.41
ClinPred		0.012	T
GERP RS		6.0
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs183145687; hg19: chr1-114372630;