NM_002834.5:c.1391G>A

Variant names:

• chr12-112488454-G-A
• NM_002834.5:c.1391G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_002834.5(PTPN11):​c.1391G>A​(p.Gly464Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1391G>A	p.Gly464Asp	missense_variant	Exon 12 of 16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1403G>A	p.Gly468Asp	missense_variant	Exon 12 of 16		NP_001317366.1
PTPN11	NM_001374625.1	c.1388G>A	p.Gly463Asp	missense_variant	Exon 12 of 16		NP_001361554.1
PTPN11	XM_011538613.3	c.1400G>A	p.Gly467Asp	missense_variant	Exon 12 of 16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1391G>A	p.Gly464Asp	missense_variant	Exon 12 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1403G>A	p.Gly468Asp	missense_variant	Exon 12 of 15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.404G>A	p.Gly135Asp	missense_variant	Exon 4 of 5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.96		Loss of catalytic residue at G462 (P = 0.0589);.;.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		1.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112926258; COSMIC: COSV61013648; COSMIC: COSV61013648;