rs3741983

Variant names:

• chr12-112502049-C-T
• rs3741983
• NM_002834.5:c.1600-95C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-112502049-C-T
• chr12-112502049-C-A
• chr12-112502049-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002834.5(PTPN11):​c.1600-95C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 938,236 control chromosomes in the GnomAD database, including 47,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.37 (15327 hom., cov: 32)
  • Exomes 𝑓: 0.23 (32404 hom.)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.93
• Publications: 15 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), Genomics England PanelApp, G2P
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for PTPN11 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-112502049-C-T is Benign according to our data. Variant chr12-112502049-C-T is described in ClinVar as Benign. ClinVar VariationId is 40569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.1600-95C>T		intron	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.1612-95C>T		intron	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1597-95C>T		intron	N/A	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1600-95C>T		intron	N/A	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1612-95C>T		intron	N/A	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000690210.1		c.1600-95C>T		intron	N/A	ENSP00000509272.1	A0A8I5KW48

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55917 AN: 151820 Hom.: 15287 Cov.: 32

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.234 AC: 183797 AN: 786298 Hom.: 32404 AF XY: 0.231 AC XY: 95196 AN XY: 411626

African (AFR) AF: 0.725 AC: 13733 AN: 18948

American (AMR) AF: 0.362 AC: 12154 AN: 33548

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2237 AN: 21060

East Asian (EAS) AF: 0.828 AC: 28127 AN: 33988

South Asian (SAS) AF: 0.274 AC: 17987 AN: 65694

European-Finnish (FIN) AF: 0.156 AC: 7746 AN: 49636

Middle Eastern (MID) AF: 0.294 AC: 849 AN: 2890

European-Non Finnish (NFE) AF: 0.174 AC: 91146 AN: 523052

Other (OTH) AF: 0.262 AC: 9818 AN: 37482

GnomAD4 genome AF: 0.369 AC: 56013 AN: 151938 Hom.: 15327 Cov.: 32 AF XY: 0.368 AC XY: 27312 AN XY: 74274

African (AFR) AF: 0.725 AC: 30036 AN: 41454

American (AMR) AF: 0.340 AC: 5191 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3468

East Asian (EAS) AF: 0.851 AC: 4407 AN: 5180

South Asian (SAS) AF: 0.297 AC: 1430 AN: 4808

European-Finnish (FIN) AF: 0.153 AC: 1614 AN: 10546

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.178 AC: 12058 AN: 67918

Other (OTH) AF: 0.336 AC: 709 AN: 2108

Alfa AF: 0.260 Hom.: 1620

Bravo AF: 0.405

Asia WGS AF: 0.525 AC: 1826 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.14
DANN	Benign	0.21
PhyloP100		-1.9
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3741983;

hg19: chr12-112939853;