13-19426462-G-A

Position:

• chr13-19426462-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395978.1(TPTE2):​c.1358C>T​(p.Pro453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPTE2 NM_001395978.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.101

Genes affected

TPTE2 (HGNC:17299): (transmembrane phosphoinositide 3-phosphatase and tensin homolog 2) TPIP is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of inositol phospholipids.[supplied by OMIM, Jul 2002]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21562985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPTE2	NM_001395978.1	c.1358C>T	p.Pro453Leu	missense_variant	21/23	ENST00000697147.1	NP_001382907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPTE2	ENST00000697147.1	c.1358C>T	p.Pro453Leu	missense_variant	21/23		NM_001395978.1	ENSP00000513136	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 14, 2023

The c.1358C>T (p.P453L) alteration is located in exon 19 (coding exon 18) of the TPTE2 gene. This alteration results from a C to T substitution at nucleotide position 1358, causing the proline (P) at amino acid position 453 to be replaced by a leucine (L). 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	0.070
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.27
DANN	Benign	0.37
DEOGEN2	Uncertain	0.56	.;D;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.20	T;T;T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.22	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0010	.;B;B;.;B
Vest4		0.092
MutPred		0.54		.;Gain of catalytic residue at G451 (P = 0.0013);.;.;.;
MVP		0.22
MPC		0.27
ClinPred		0.035	T
GERP RS		-2.6
Varity_R		0.029
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr13-20000602; COSMIC: COSV105045048;