rs201957261

Positions:

• chr12-112504777-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002834.5(PTPN11):​c.*13A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,549,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: PTPN11 NM_002834.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.522

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-112504777-A-G is Benign according to our data. Variant chr12-112504777-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112504777-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.*13A>G		3_prime_UTR_variant	15/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.*13A>G		3_prime_UTR_variant	15/16		NP_001317366.1
PTPN11	NM_001374625.1	c.*13A>G		3_prime_UTR_variant	15/16		NP_001361554.1
PTPN11	XM_011538613.3	c.*13A>G		3_prime_UTR_variant	15/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.*13A>G		3_prime_UTR_variant	15/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.*13A>G		downstream_gene_variant		5		ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000332 AC: 83 AN: 250256 Hom.: 0 AF XY: 0.000318 AC XY: 43 AN XY: 135298

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000593

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000468 AC: 653 AN: 1396734 Hom.: 0 Cov.: 29 AF XY: 0.000482 AC XY: 336 AN XY: 697766

Gnomad4 AFR exome AF: 0.0000940

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000573

Gnomad4 OTH exome AF: 0.000498

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74498

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 13, 2015	c.*13A>G in the 3'UTR of PTPN11: This variant is not expected to have clinical significance because it has been identified in 0.1% (43/62072) of European chrom osomes by the Exome Aggregation Constortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201957261). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.47
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201957261; hg19: chr12-112942581;