Genetic Variant TPTE2:p.Arg407His (chr13-19432475-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001395978.1(TPTE2):c.1220G>A(p.Arg407His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,573,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R407C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000078 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TPTE2
NM_001395978.1 missense, splice_region

Scores

Splicing: ADA: 0.000008939

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.30

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08621392).

BP6

Variant 13-19432475-C-T is Benign according to our data. Variant chr13-19432475-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3972757.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1220G>A	p.Arg407His	missense splice_region	Exon 19 of 23	NP_001382907.1	Q6XPS3-1
TPTE2	NM_199254.3		c.1220G>A	p.Arg407His	missense splice_region	Exon 17 of 21	NP_954863.2	Q6XPS3-1
TPTE2	NM_130785.4		c.989G>A	p.Arg330His	missense splice_region	Exon 14 of 18	NP_570141.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPTE2	ENST00000697147.1	MANE Select	c.1220G>A	p.Arg407His	missense splice_region	Exon 19 of 23	ENSP00000513136.1	Q6XPS3-1
TPTE2	ENST00000390680.2	TSL:1	c.989G>A	p.Arg330His	missense splice_region	Exon 14 of 18	ENSP00000375098.2	Q6XPS3-3
TPTE2	ENST00000696858.2		c.1220G>A	p.Arg407His	missense splice_region	Exon 18 of 22	ENSP00000512931.1	Q6XPS3-1

Frequencies

GnomAD3 genomes

AF:

0.00000785

AC:

AN:

127402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000168

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000406

AC:

AN:

246472

AF XY:

0.0000300

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1445686

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33122

American (AMR)

AF:

0.000136

AC:

AN:

44086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

39038

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4594

European-Non Finnish (NFE)

AF:

0.00000635

AC:

AN:

1102138

Other (OTH)

AF:

0.0000168

AC:

AN:

59542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000785

AC:

AN:

127402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

60768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35314

American (AMR)

AF:

0.00

AC:

AN:

11598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3120

East Asian (EAS)

AF:

0.00

AC:

AN:

4296

South Asian (SAS)

AF:

0.00

AC:

AN:

3456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

59696

Other (OTH)

AF:

0.00

AC:

AN:

1658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

Benign

0.069

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.38

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.60

M_CAP

Benign

0.013

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-1.2

PhyloP100

1.3

PrimateAI

Benign

0.29

PROVEAN

Benign

2.6

REVEL

Benign

0.15

Sift

Benign

0.46

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.22

MVP

0.39

MPC

0.33

ClinPred

0.023

GERP RS

1.4

Varity_R

0.015

gMVP

0.28

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000089

dbscSNV1_RF

Benign

0.0020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over