rs41279092

Variant names:

• chr12-112486902-G-A
• rs41279092
• ENST00000392597.5:c.*269G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-112486902-G-A
• chr12-112486902-G-T

Variant summary

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

The NM_080601.3(PTPN11):​c.*269G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,393,526 control chromosomes in the GnomAD database, including 1,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (180 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1765 hom.)
• Consequence: PTPN11 NM_080601.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome

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

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

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

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-112486902-G-A is Benign according to our data. Variant chr12-112486902-G-A is described in ClinVar as Benign. ClinVar VariationId is 561856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080601.3. 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.1379+273G>A		intron	N/A	NP_002825.3
	PTPN11	NM_080601.3		c.*269G>A		3_prime_UTR	Exon 11 of 11	NP_542168.1	Q06124-3
	PTPN11	NM_001330437.2		c.1391+273G>A		intron	N/A	NP_001317366.1	Q06124-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000392597.5	TSL:1	c.*269G>A		3_prime_UTR	Exon 11 of 11	ENSP00000376376.1	Q06124-3
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1379+273G>A		intron	N/A	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1391+273G>A		intron	N/A	ENSP00000489597.1	Q06124-1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5986 AN: 152150 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0506

Gnomad OTH AF: 0.0330

GnomAD4 exome AF: 0.0490 AC: 60810 AN: 1241258 Hom.: 1765 Cov.: 30 AF XY: 0.0498 AC XY: 29816 AN XY: 598224

African (AFR) AF: 0.00624 AC: 172 AN: 27584

American (AMR) AF: 0.0233 AC: 425 AN: 18228

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 584 AN: 18018

East Asian (EAS) AF: 0.000252 AC: 8 AN: 31798

South Asian (SAS) AF: 0.0778 AC: 4587 AN: 58982

European-Finnish (FIN) AF: 0.0938 AC: 2529 AN: 26972

Middle Eastern (MID) AF: 0.0393 AC: 133 AN: 3382

European-Non Finnish (NFE) AF: 0.0498 AC: 50023 AN: 1005238

Other (OTH) AF: 0.0460 AC: 2349 AN: 51056

GnomAD4 genome AF: 0.0393 AC: 5982 AN: 152268 Hom.: 180 Cov.: 32 AF XY: 0.0422 AC XY: 3139 AN XY: 74436

African (AFR) AF: 0.00712 AC: 296 AN: 41564

American (AMR) AF: 0.0306 AC: 468 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0785 AC: 379 AN: 4828

European-Finnish (FIN) AF: 0.101 AC: 1069 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0507 AC: 3445 AN: 68012

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0439 Hom.: 226

Bravo AF: 0.0309

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.67
PhyloP100		0.038
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: rs41279092; hg19: chr12-112924706;