ENST00000392597:c.-179G>C

Variant names:

• chr12-112418933-G-C
• rs545369072
• ENST00000392597.5:c.-179G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000392597.5(PTPN11):​c.-179G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 711,260 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 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: PTPN11 ENST00000392597.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.389
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392597.5. 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.-179G>C		upstream_gene	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.-179G>C		upstream_gene	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.-179G>C		upstream_gene	N/A	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000392597.5	TSL:1	c.-179G>C		5_prime_UTR	Exon 1 of 11	ENSP00000376376.1	Q06124-3
	PTPN11	ENST00000690210.1		c.-179G>C		5_prime_UTR	Exon 1 of 17	ENSP00000509272.1	A0A8I5KW48
	PTPN11	ENST00000882517.1		c.-179G>C		5_prime_UTR	Exon 1 of 16	ENSP00000552576.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 18 AN: 558952 Hom.: 0 Cov.: 7 AF XY: 0.0000237 AC XY: 7 AN XY: 295252

African (AFR) AF: 0.00 AC: 0 AN: 12162

American (AMR) AF: 0.00 AC: 0 AN: 24684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17670

East Asian (EAS) AF: 0.00 AC: 0 AN: 25418

South Asian (SAS) AF: 0.0000360 AC: 2 AN: 55614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31756

Middle Eastern (MID) AF: 0.000414 AC: 1 AN: 2416

European-Non Finnish (NFE) AF: 0.0000361 AC: 13 AN: 359698

Other (OTH) AF: 0.0000677 AC: 2 AN: 29534

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions

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	-0.44
CADD	Benign	16
DANN	Benign	0.92
PhyloP100		0.39
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs545369072; hg19: chr12-112856737;