rs144391508

Variant names:

• chr12-112477621-T-C
• rs144391508
• NM_002834.5:c.854-30T>C

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.854-30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,561,580 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0094 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (414 hom.)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.390

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]

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-112477621-T-C is Benign according to our data. Variant chr12-112477621-T-C is described in ClinVar as [Benign]. Clinvar id is 40531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.854-30T>C		intron_variant	Intron 7 of 15	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.854-30T>C		intron_variant	Intron 7 of 15	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.854-30T>C		intron_variant	Intron 7 of 14	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152184 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0823

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0180 AC: 4523 AN: 251170 AF XY: 0.0136

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00426 AC: 6007 AN: 1409278 Hom.: 414 Cov.: 27 AF XY: 0.00357 AC XY: 2512 AN XY: 704228

Gnomad4 AFR exome AF: 0.00146 AC: 47 AN: 32282

Gnomad4 AMR exome AF: 0.125 AC: 5576 AN: 44666

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25822

Gnomad4 EAS exome AF: 0.000913 AC: 36 AN: 39450

Gnomad4 SAS exome AF: 0.000470 AC: 40 AN: 85144

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53400

Gnomad4 NFE exome AF: 0.0000666 AC: 71 AN: 1065796

Gnomad4 Remaining exome AF: 0.00400 AC: 234 AN: 58542

GnomAD4 genome AF: 0.00936 AC: 1425 AN: 152302 Hom.: 70 Cov.: 32 AF XY: 0.0109 AC XY: 809 AN XY: 74466

Gnomad4 AFR AF: 0.00245 AC: 0.00245428 AN: 0.00245428

Gnomad4 AMR AF: 0.0829 AC: 0.0828859 AN: 0.0828859

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00135 AC: 0.00134875 AN: 0.00134875

Gnomad4 SAS AF: 0.00104 AC: 0.0010352 AN: 0.0010352

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000191 AC: 0.00019107 AN: 0.00019107

Gnomad4 OTH AF: 0.0152 AC: 0.0151659 AN: 0.0151659

Alfa AF: 0.00457 Hom.: 5

Bravo AF: 0.0158

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PTPN11 c.854-30T>C variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4526/276876 control chromosomes (320 homozygotes) (gnomAD), predominantly observed in the Latino subpopulation at a frequency of 0.126476 (4349/34386). This frequency is about 2000 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Benign:1

May 29, 2014

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.28
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs144391508; hg19: chr12-112915425; COSMIC: COSV61011589;