rs767503386

Variant names:

• chr12-112482171-C-A
• NM_002834.5:c.1190C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-112482171-C-A
• chr12-112482171-C-G
• chr12-112482171-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_002834.5(PTPN11):​c.1190C>A​(p.Thr397Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 3.65

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 6 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, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1190C>A	p.Thr397Lys	missense_variant	Exon 10 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1190C>A	p.Thr397Lys	missense_variant	Exon 10 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1190C>A	p.Thr397Lys	missense_variant	Exon 10 of 15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.182C>A	p.Thr61Lys	missense_variant	Exon 2 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	Uncertain	0.55
CardioboostCm	Benign	0.026
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.62	.;.;D;.
Eigen	Benign	-0.082
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;.;.
REVEL	Uncertain	0.59
Sift	Benign	0.56	T;T;.;.
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0080	B;B;.;.
Vest4		0.69
MutPred		0.70		Gain of disorder (P = 0.03);Gain of disorder (P = 0.03);Gain of disorder (P = 0.03);.;
MVP		0.95
MPC		1.1
ClinPred		0.60	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.83

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: chr12-112919975;