Variant 12-6957678-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_002831.6(PTPN6):c.1099G>A(p.Glu367Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000764 in 1,296,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

PTPN6
NM_002831.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.43

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]

PTPN6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, PTPN6

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN6	NM_002831.6 linkuse as main transcript	c.1099G>A	p.Glu367Lys	missense_variant	10/16	ENST00000318974.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN6	ENST00000318974.14 linkuse as main transcript	c.1099G>A	p.Glu367Lys	missense_variant	10/16	1	NM_002831.6	P1	P29350-1
PTPN6	ENST00000456013.5 linkuse as main transcript	c.1099G>A	p.Glu367Lys	missense_variant	10/16	1			P29350-4
PTPN6	ENST00000399448.5 linkuse as main transcript	c.1105G>A	p.Glu369Lys	missense_variant	10/16	1			P29350-3
PTPN6	ENST00000416215.6 linkuse as main transcript	n.1507G>A		non_coding_transcript_exon_variant	9/15	2

Frequencies

GnomAD3 genomes

AF:

0.000274

AC:

AN:

142346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000779

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000277

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:

0.0000309

Gnomad OTH

AF:

0.000999

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

249000

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1154058

Hom.:

Cov.:

AF XY:

0.0000504

AC XY:

AN XY:

575390

show subpopulations

Gnomad4 AFR exome

AF:

0.000913

Gnomad4 AMR exome

AF:

0.000239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000280

Gnomad4 OTH exome

AF:

0.0000236

GnomAD4 genome

AF:

0.000274

AC:

AN:

142346

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

69122

show subpopulations

Gnomad4 AFR

AF:

0.000779

Gnomad4 AMR

AF:

0.000277

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000309

Gnomad4 OTH

AF:

0.000999

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.000499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.1099G>A (p.E367K) alteration is located in exon 10 (coding exon 10) of the PTPN6 gene. This alteration results from a G to A substitution at nucleotide position 1099, causing the glutamic acid (E) at amino acid position 367 to be replaced by a lysine (K). 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

0.29

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Uncertain

0.26

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.010

D;D;T

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.97

.;D;.

Vest4

0.60

MVP

0.68

MPC

1.7

ClinPred

0.23

GERP RS

5.1

Varity_R

0.37

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over