chr12-112471536-T-C

Variant names:

• chr12-112471536-T-C
• rs12423190
• NM_002834.5:c.757-1408T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002834.5(PTPN11):​c.757-1408T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 151,602 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.089 (648 hom., cov: 31)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.757-1408T>C		intron_variant	Intron 6 of 15	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.757-1408T>C		intron_variant	Intron 6 of 15	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.757-1408T>C		intron_variant	Intron 6 of 14	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13438 AN: 151484 Hom.: 648 Cov.: 31

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0805

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0887 AC: 13444 AN: 151602 Hom.: 648 Cov.: 31 AF XY: 0.0896 AC XY: 6637 AN XY: 74076

African (AFR) AF: 0.0980 AC: 4049 AN: 41302

American (AMR) AF: 0.0574 AC: 874 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1189 AN: 5142

South Asian (SAS) AF: 0.126 AC: 606 AN: 4810

European-Finnish (FIN) AF: 0.0993 AC: 1034 AN: 10408

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5378 AN: 67926

Other (OTH) AF: 0.0792 AC: 167 AN: 2108

Alfa AF: 0.0798 Hom.: 459

Bravo AF: 0.0880

Asia WGS AF: 0.205 AC: 708 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.56
PhyloP100		0.014
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: rs12423190; hg19: chr12-112909340;