rs190247406

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_002831.6(PTPN6):​c.1083C>A​(p.Cys361*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000803 in 1,244,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C361C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

PTPN6
NM_002831.6 stop_gained

Scores

2
3
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.550

Publications

0 publications found
Variant links:
Genes affected
PTPN6 (HGNC:9658): (protein tyrosine phosphatase non-receptor type 6) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling. Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN6NM_002831.6 linkc.1083C>A p.Cys361* stop_gained Exon 10 of 16 ENST00000318974.14 NP_002822.2 P29350-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN6ENST00000318974.14 linkc.1083C>A p.Cys361* stop_gained Exon 10 of 16 1 NM_002831.6 ENSP00000326010.9 P29350-1
PTPN6ENST00000456013.5 linkc.1083C>A p.Cys361* stop_gained Exon 10 of 16 1 ENSP00000391592.1 P29350-4
PTPN6ENST00000399448.5 linkc.1089C>A p.Cys363* stop_gained Exon 10 of 16 1 ENSP00000382376.1 P29350-3
PTPN6ENST00000416215.6 linkn.1491C>A non_coding_transcript_exon_variant Exon 9 of 15 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
8.03e-7
AC:
1
AN:
1244644
Hom.:
0
Cov.:
49
AF XY:
0.00
AC XY:
0
AN XY:
623058
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28120
American (AMR)
AF:
0.00
AC:
0
AN:
41384
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21822
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30724
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82736
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
41368
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4992
European-Non Finnish (NFE)
AF:
0.00000106
AC:
1
AN:
943598
Other (OTH)
AF:
0.00
AC:
0
AN:
49900
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.044
FATHMM_MKL
Uncertain
0.83
D
PhyloP100
0.55
Vest4
0.97
GERP RS
1.4
Mutation Taster
=1/199
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs190247406; hg19: chr12-7066825; API