12-112419110-A-C

Variant names:

• chr12-112419110-A-C
• NM_002834.5:c.-2A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002834.5(PTPN11):​c.-2A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,376,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PTPN11 NM_002834.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.-2A>C		5_prime_UTR_variant	Exon 1 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.-2A>C		5_prime_UTR_variant	Exon 1 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.-2A>C		upstream_gene_variant		5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000436 AC: 6 AN: 1376790 Hom.: 0 Cov.: 30 AF XY: 0.00000589 AC XY: 4 AN XY: 679448

African (AFR) AF: 0.00 AC: 0 AN: 29188

American (AMR) AF: 0.00 AC: 0 AN: 34694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24638

East Asian (EAS) AF: 0.00 AC: 0 AN: 34116

South Asian (SAS) AF: 0.0000773 AC: 6 AN: 77576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072516

Other (OTH) AF: 0.00 AC: 0 AN: 57134

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-2A>C variant is located in the 5' untranslated region (5’ UTR) of the PTPN11 gene. This variant results from an A to C substitution 2 nucleotides upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.87
PhyloP100		2.4
PromoterAI		-0.057	Neutral

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

hg19: chr12-112856914;