dbSNP rs1190975831: TPTE2:p.Arg489Ser (chr13-19423164-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001395978.1(TPTE2):c.1467G>C(p.Arg489Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R489K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TPTE2
NM_001395978.1 missense, splice_region

Scores

Splicing: ADA: 0.01078

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.447

Publications

0 publications found

Variant links:

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]

TPTE2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPTE2	NM_001395978.1	MANE Select	c.1467G>C	p.Arg489Ser	missense splice_region	Exon 23 of 23	NP_001382907.1	Q6XPS3-1
TPTE2	NM_199254.3		c.1467G>C	p.Arg489Ser	missense splice_region	Exon 21 of 21	NP_954863.2	Q6XPS3-1
TPTE2	NM_130785.4		c.1236G>C	p.Arg412Ser	missense splice_region	Exon 18 of 18	NP_570141.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPTE2	ENST00000697147.1	MANE Select	c.1467G>C	p.Arg489Ser	missense splice_region	Exon 23 of 23	ENSP00000513136.1	Q6XPS3-1
TPTE2	ENST00000390680.2	TSL:1	c.1236G>C	p.Arg412Ser	missense splice_region	Exon 18 of 18	ENSP00000375098.2	Q6XPS3-3
TPTE2	ENST00000696858.2		c.1467G>C	p.Arg489Ser	missense splice_region	Exon 22 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446002

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32322

American (AMR)

AF:

0.00

AC:

AN:

41880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

38982

South Asian (SAS)

AF:

0.00

AC:

AN:

82818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105658

Other (OTH)

AF:

0.00

AC:

AN:

59702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.95

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.055

MutationAssessor

Uncertain

2.2

PhyloP100

0.45

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.53

Sift

Benign

0.30

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.85

MutPred

0.58

Gain of catalytic residue at L490 (P = 0)

MVP

0.72

MPC

0.85

ClinPred

0.84

GERP RS

1.2

Varity_R

0.48

gMVP

0.64

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.011

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over