9-109408362-T-G

Position:

• chr9-109408362-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002829.4(PTPN3):​c.1594A>C​(p.Lys532Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN3 NM_002829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

Genes affected

PTPN3 (HGNC:9655): (protein tyrosine phosphatase non-receptor type 3) 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 protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins. P97, a cell cycle regulator involved in a variety of membrane related functions, has been shown to be a substrate of this PTP. This PTP was also found to interact with, and be regulated by adaptor protein 14-3-3 beta. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN3	NM_002829.4	c.1594A>C	p.Lys532Gln	missense_variant	17/26	ENST00000374541.4	NP_002820.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN3	ENST00000374541.4	c.1594A>C	p.Lys532Gln	missense_variant	17/26	5	NM_002829.4	ENSP00000363667.1
PTPN3	ENST00000412145.5	c.1201A>C	p.Lys401Gln	missense_variant	12/21	1		ENSP00000416654.1
PTPN3	ENST00000446349.5	c.1066A>C	p.Lys356Gln	missense_variant	11/20	1		ENSP00000395384.1
PTPN3	ENST00000262539.7	c.1594A>C	p.Lys532Gln	missense_variant	17/26	5		ENSP00000262539.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437440 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 2 AN XY: 713684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.1594A>C (p.K532Q) alteration is located in exon 17 (coding exon 16) of the PTPN3 gene. This alteration results from a A to C substitution at nucleotide position 1594, causing the lysine (K) at amino acid position 532 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	.;.;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	.;.;.;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.016	D;D;.;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.67
MutPred		0.47		.;.;Loss of ubiquitination at K532 (P = 0.0326);Loss of ubiquitination at K532 (P = 0.0326);
MVP		0.73
MPC		0.86
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.38

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: chr9-112170642;