13-19430469-G-A

Variant names:

• chr13-19430469-G-A
• rs149205749
• NM_001395978.1:c.1301C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001395978.1(TPTE2):​c.1301C>T​(p.Ser434Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: TPTE2 NM_001395978.1 missense, splice_region
• Scores: Splicing: ADA: 0.0002660
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.02
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06141165).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395978.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPTE2	NM_001395978.1	MANE Select	c.1301C>T	p.Ser434Leu	missense splice_region	Exon 20 of 23	NP_001382907.1	Q6XPS3-1
	TPTE2	NM_199254.3		c.1301C>T	p.Ser434Leu	missense splice_region	Exon 18 of 21	NP_954863.2	Q6XPS3-1
	TPTE2	NM_130785.4		c.1070C>T	p.Ser357Leu	missense splice_region	Exon 15 of 18	NP_570141.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPTE2	ENST00000697147.1	MANE Select	c.1301C>T	p.Ser434Leu	missense splice_region	Exon 20 of 23	ENSP00000513136.1	Q6XPS3-1
	TPTE2	ENST00000390680.2	TSL:1	c.1070C>T	p.Ser357Leu	missense splice_region	Exon 15 of 18	ENSP00000375098.2	Q6XPS3-3
	TPTE2	ENST00000696858.2		c.1301C>T	p.Ser434Leu	missense splice_region	Exon 19 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000616 AC: 15 AN: 243412 AF XY: 0.0000532

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000937

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000144 AC: 209 AN: 1454084 Hom.: 1 Cov.: 29 AF XY: 0.000149 AC XY: 108 AN XY: 723448

African (AFR) AF: 0.0000907 AC: 3 AN: 33076

American (AMR) AF: 0.000117 AC: 5 AN: 42620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39528

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000166 AC: 184 AN: 1109160

Other (OTH) AF: 0.000166 AC: 10 AN: 60082

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74244

African (AFR) AF: 0.000145 AC: 6 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.089
DANN	Benign	0.52
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.15	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.53		Gain of catalytic residue at S434 (P = 0)
MVP		0.23
MPC		0.24
ClinPred		0.039	T
GERP RS		-4.5
Varity_R		0.036
gMVP		0.43
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149205749; hg19: chr13-20004609;