12-112495731-G-A

Variant names:

• chr12-112495731-G-A
• rs7313360
• NM_002834.5:c.1600-6413G>A

Variant summary

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

The NM_002834.5(PTPN11):​c.1600-6413G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,122 control chromosomes in the GnomAD database, including 5,479 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 0.21 (5479 hom., cov: 32)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 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.1600-6413G>A		intron	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.1612-6413G>A		intron	N/A	NP_001317366.1
	PTPN11	NM_001374625.1		c.1597-6413G>A		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.1600-6413G>A		intron	N/A	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.1612-6413G>A		intron	N/A	ENSP00000489597.1
	PTPN11	ENST00000690210.1		c.1600-6413G>A		intron	N/A	ENSP00000509272.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31969 AN: 152004 Hom.: 5476 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0947

Gnomad OTH AF: 0.193

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

GnomAD4 genome AF: 0.210 AC: 32015 AN: 152122 Hom.: 5479 Cov.: 32 AF XY: 0.216 AC XY: 16091 AN XY: 74366

African (AFR) AF: 0.351 AC: 14580 AN: 41482

American (AMR) AF: 0.236 AC: 3612 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3470

East Asian (EAS) AF: 0.852 AC: 4399 AN: 5166

South Asian (SAS) AF: 0.246 AC: 1188 AN: 4822

European-Finnish (FIN) AF: 0.112 AC: 1187 AN: 10584

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0947 AC: 6440 AN: 67998

Other (OTH) AF: 0.192 AC: 405 AN: 2114

Alfa AF: 0.158 Hom.: 363

Bravo AF: 0.231

Asia WGS AF: 0.483 AC: 1677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.15
PhyloP100		-0.54
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: rs7313360; hg19: chr12-112933535;