NM_002834.5:c.854-21C>T

Variant names:

• chr12-112477630-C-T
• rs41279090
• NM_002834.5:c.854-21C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.278
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.854-21C>T		intron	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.854-21C>T		intron	N/A	NP_001317366.1
	PTPN11	NM_001374625.1		c.851-21C>T		intron	N/A	NP_001361554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.854-21C>T		intron	N/A	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.854-21C>T		intron	N/A	ENSP00000489597.1
	PTPN11	ENST00000392597.5	TSL:1	c.854-21C>T		intron	N/A	ENSP00000376376.1

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8569 AN: 151944 Hom.: 315 Cov.: 32

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

GnomAD2 exomes AF: 0.0581 AC: 14589 AN: 251218 AF XY: 0.0597

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 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.: 30 AF XY: 0.0712 AC XY: 50830 AN XY: 714394

African (AFR) AF: 0.0220 AC: 721 AN: 32812

American (AMR) AF: 0.0497 AC: 2221 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1559 AN: 25984

East Asian (EAS) AF: 0.000253 AC: 10 AN: 39584

South Asian (SAS) AF: 0.0482 AC: 4120 AN: 85562

European-Finnish (FIN) AF: 0.0356 AC: 1903 AN: 53410

Middle Eastern (MID) AF: 0.114 AC: 494 AN: 4316

European-Non Finnish (NFE) AF: 0.0810 AC: 88024 AN: 1086588

Other (OTH) AF: 0.0685 AC: 4065 AN: 59376

GnomAD4 genome AF: 0.0563 AC: 8562 AN: 152064 Hom.: 315 Cov.: 32 AF XY: 0.0545 AC XY: 4048 AN XY: 74324

African (AFR) AF: 0.0237 AC: 984 AN: 41488

American (AMR) AF: 0.0664 AC: 1013 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0461 AC: 222 AN: 4820

European-Finnish (FIN) AF: 0.0404 AC: 426 AN: 10550

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0793 AC: 5389 AN: 67988

Other (OTH) AF: 0.0825 AC: 174 AN: 2108

Alfa AF: 0.0678 Hom.: 279

Bravo AF: 0.0573

Asia WGS AF: 0.0200 AC: 73 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 28, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Metachondromatosis Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juvenile myelomonocytic leukemia Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome Benign:1

Sep 25, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		-0.28
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41279090; hg19: chr12-112915434; COSMIC: COSV61012275;