chr2-119809969-C-G

Variant names:

• chr2-119809969-C-G
• rs1247625783
• NM_002830.4:c.116C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002830.4(PTPN4):​c.116C>G​(p.Thr39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,456,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T39A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PTPN4 NM_002830.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

Genes affected

PTPN4 (HGNC:9656): (protein tyrosine phosphatase non-receptor type 4) 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. This PTP has been shown to interact with glutamate receptor delta 2 and epsilon subunits, and is thought to play a role in signalling downstream of the glutamate receptors through tyrosine dephosphorylation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23441947).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN4	NM_002830.4	c.116C>G	p.Thr39Ser	missense_variant	Exon 2 of 27	ENST00000263708.7	NP_002821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN4	ENST00000263708.7	c.116C>G	p.Thr39Ser	missense_variant	Exon 2 of 27	1	NM_002830.4	ENSP00000263708.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456120 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724106

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.116C>G (p.T39S) alteration is located in exon 2 (coding exon 1) of the PTPN4 gene. This alteration results from a C to G substitution at nucleotide position 116, causing the threonine (T) at amino acid position 39 to be replaced by a serine (S). 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	0.097
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0060
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.47	N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.34
MutPred		0.62		Gain of disorder (P = 0.1237);Gain of disorder (P = 0.1237);Gain of disorder (P = 0.1237);
MVP		0.49
MPC		0.42
ClinPred		0.56	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs1247625783; hg19: chr2-120567545;