rs184743462

Variant names:

• chr12-112486649-C-T
• rs184743462
• ENST00000392597.5:c.*16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000392597.5(PTPN11):​c.*16C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,611,546 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (11 hom.)
• Consequence: PTPN11 ENST00000392597.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.493
• Publications: 4 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=-0.88).
• BP6: Variant 12-112486649-C-T is Benign according to our data. Variant chr12-112486649-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000637 (97/152350) while in subpopulation EAS AF = 0.00809 (42/5192). AF 95% confidence interval is 0.00615. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 97 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392597.5. 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.1379+20C>T		intron	N/A	NP_002825.3
	PTPN11	NM_080601.3		c.*16C>T		3_prime_UTR	Exon 11 of 11	NP_542168.1
	PTPN11	NM_001330437.2		c.1391+20C>T		intron	N/A	NP_001317366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000392597.5	TSL:1	c.*16C>T		3_prime_UTR	Exon 11 of 11	ENSP00000376376.1
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1379+20C>T		intron	N/A	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.1391+20C>T		intron	N/A	ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00136 AC: 334 AN: 245884 AF XY: 0.00130

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00727

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000757 AC: 1105 AN: 1459196 Hom.: 11 Cov.: 31 AF XY: 0.000734 AC XY: 533 AN XY: 725868

African (AFR) AF: 0.0000599 AC: 2 AN: 33396

American (AMR) AF: 0.00258 AC: 115 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26100

East Asian (EAS) AF: 0.0157 AC: 622 AN: 39662

South Asian (SAS) AF: 0.000744 AC: 64 AN: 85988

European-Finnish (FIN) AF: 0.00156 AC: 83 AN: 53312

Middle Eastern (MID) AF: 0.000235 AC: 1 AN: 4254

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111752

Other (OTH) AF: 0.000948 AC: 57 AN: 60158

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74514

African (AFR) AF: 0.0000721 AC: 3 AN: 41594

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00809 AC: 42 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000589

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Juvenile myelomonocytic leukemia (1)
-	-	1	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
-	-	1	Metachondromatosis (1)
-	-	1	not provided (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism

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: rs184743462; hg19: chr12-112924453;