chr12-112504549-G-A

Variant names:

• chr12-112504549-G-A
• rs4767860
• NM_002834.5:c.1713-146G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002834.5(PTPN11):​c.1713-146G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 664,276 control chromosomes in the GnomAD database, including 8,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (1313 hom., cov: 33)
  • Exomes 𝑓: 0.063 (7282 hom.)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.698
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-112504549-G-A is Benign according to our data. Variant chr12-112504549-G-A is described in ClinVar as Benign. ClinVar VariationId is 1293594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1713-146G>A		intron_variant	Intron 14 of 15	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1725-146G>A		intron_variant	Intron 14 of 15		NP_001317366.1
PTPN11	NM_001374625.1	c.1710-146G>A		intron_variant	Intron 14 of 15		NP_001361554.1
PTPN11	XM_011538613.3	c.1722-146G>A		intron_variant	Intron 14 of 15		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1713-146G>A		intron_variant	Intron 14 of 15	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1725-146G>A		intron_variant	Intron 14 of 14	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8593 AN: 152132 Hom.: 1318 Cov.: 33

Gnomad AFR AF: 0.0564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.0964

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.0641

GnomAD4 exome AF: 0.0634 AC: 32488 AN: 512026 Hom.: 7282 AF XY: 0.0620 AC XY: 17033 AN XY: 274666

African (AFR) AF: 0.0527 AC: 716 AN: 13582

American (AMR) AF: 0.195 AC: 5137 AN: 26386

Ashkenazi Jewish (ASJ) AF: 0.00499 AC: 84 AN: 16822

East Asian (EAS) AF: 0.643 AC: 19585 AN: 30456

South Asian (SAS) AF: 0.0784 AC: 4230 AN: 53980

European-Finnish (FIN) AF: 0.00335 AC: 148 AN: 44178

Middle Eastern (MID) AF: 0.0300 AC: 65 AN: 2164

European-Non Finnish (NFE) AF: 0.00343 AC: 1019 AN: 296788

Other (OTH) AF: 0.0544 AC: 1504 AN: 27670

GnomAD4 genome AF: 0.0565 AC: 8598 AN: 152250 Hom.: 1313 Cov.: 33 AF XY: 0.0630 AC XY: 4688 AN XY: 74438

African (AFR) AF: 0.0563 AC: 2340 AN: 41550

American (AMR) AF: 0.144 AC: 2201 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.615 AC: 3179 AN: 5172

South Asian (SAS) AF: 0.0971 AC: 468 AN: 4818

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10622

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68016

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0156 Hom.: 184

Bravo AF: 0.0718

Asia WGS AF: 0.245 AC: 848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.66
DANN	Benign	0.56
PhyloP100		-0.70
Mutation Taster		=99/1	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: rs4767860; hg19: chr12-112942353;