rs886048963

Variant names:

• chr12-112418867-C-G
• rs886048963
• ENST00000531326.1:n.359C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000531326.1(PTPN11):​n.359C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 510,242 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: PTPN11 ENST00000531326.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.06
• Publications: 0 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]

RPL6 (HGNC:10362): (ribosomal protein L6) This gene encodes a protein component of the 60S ribosomal subunit. This protein can bind specifically to domain C of the tax-responsive enhancer element of human T-cell leukemia virus type 1, and may participate in tax-mediated transactivation of transcription. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000307 (110/357908) while in subpopulation EAS AF = 0.00471 (109/23154). AF 95% confidence interval is 0.00399. There are 0 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 3. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000531326.1. 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.-245C>G		upstream_gene	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.-245C>G		upstream_gene	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.-245C>G		upstream_gene	N/A	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000531326.1	TSL:4	n.359C>G		non_coding_transcript_exon	Exon 2 of 2
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.-245C>G		upstream_gene	N/A	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.-245C>G		upstream_gene	N/A	ENSP00000489597.1	Q06124-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000307 AC: 110 AN: 357908 Hom.: 0 Cov.: 3 AF XY: 0.000244 AC XY: 46 AN XY: 188642

African (AFR) AF: 0.00 AC: 0 AN: 7866

American (AMR) AF: 0.00 AC: 0 AN: 8566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11336

East Asian (EAS) AF: 0.00471 AC: 109 AN: 23154

South Asian (SAS) AF: 0.00 AC: 0 AN: 34398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 222216

Other (OTH) AF: 0.0000463 AC: 1 AN: 21596

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41596

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	LEOPARD syndrome 1 (1)
-	1	-	Metachondromatosis (1)
-	1	-	Noonan syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.81
PhyloP100		1.1
PromoterAI		-0.26	Neutral

Splicing

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

Other links and lift over

dbSNP: rs886048963; hg19: chr12-112856671;