12-112477630-C-T

Position:

chr12-112477630-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002834.5(PTPN11):c.854-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 1,584,378 control chromosomes in the GnomAD database, including 4,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 315 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4080 hom. )

Consequence

PTPN11
NM_002834.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.278

Variant links:

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) 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. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 12-112477630-C-T is Benign according to our data. Variant chr12-112477630-C-T is described in ClinVar as [Benign]. Clinvar id is 40532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.854-21C>T		intron_variant		ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.854-21C>T		intron_variant		1	NM_002834.5	ENSP00000340944	A1	Q06124-2

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8569

AN:

151944

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.0553

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0460

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.0793

Gnomad OTH

AF:

0.0844

GnomAD3 exomes

AF:

0.0581

AC:

14589

AN:

251218

Hom.:

580

AF XY:

0.0597

AC XY:

8101

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.0212

Gnomad AMR exome

AF:

0.0482

Gnomad ASJ exome

AF:

0.0589

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0494

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0820

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0720

AC:

103117

AN:

1432314

Hom.:

4080

Cov.:

AF XY:

0.0712

AC XY:

50830

AN XY:

714394

show subpopulations

Gnomad4 AFR exome

AF:

0.0220

Gnomad4 AMR exome

AF:

0.0497

Gnomad4 ASJ exome

AF:

0.0600

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.0482

Gnomad4 FIN exome

AF:

0.0356

Gnomad4 NFE exome

AF:

0.0810

Gnomad4 OTH exome

AF:

0.0685

GnomAD4 genome

AF:

0.0563

AC:

8562

AN:

152064

Hom.:

315

Cov.:

AF XY:

0.0545

AC XY:

4048

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0237

Gnomad4 AMR

AF:

0.0664

Gnomad4 ASJ

AF:

0.0553

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0461

Gnomad4 FIN

AF:

0.0404

Gnomad4 NFE

AF:

0.0793

Gnomad4 OTH

AF:

0.0825

Alfa

AF:

0.0574

Hom.:

120

Bravo

AF:

0.0573

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2017	Variant summary: The PTPN11 c.854-21C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40, SF2/ASF and SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 15911/276874 control chromosomes (626 homozygotes) at a frequency of 0.0574666, which is approximately 900 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Juvenile myelomonocytic leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Noonan syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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