Genetic Variant PIP4P1:p.Ala47Thr (chr14-20461187-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144568.4(PIP4P1):c.139G>A(p.Ala47Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,261,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

PIP4P1
NM_144568.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.877

Variant links:

Genes affected

PIP4P1 (HGNC:19299): (phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1) TMEM55B catalyzes the degradation of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2) by removing the 4-phosphate (Ungewickell et al., 2005 [PubMed 16365287]).[supplied by OMIM, Mar 2008]

PIP4P1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030651748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4P1	NM_144568.4 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 7	ENST00000250489.9	NP_653169.2	Q86T03-1
PIP4P1	NM_001100814.3 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 7		NP_001094284.1	Q86T03-2
PIP4P1	XM_024449739.2 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 6		XP_024305507.1
PIP4P1	XM_024449740.2 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 6		XP_024305508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIP4P1	ENST00000250489.9 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 7	1	NM_144568.4	ENSP00000250489.4	Q86T03-1
PIP4P1	ENST00000398020.6 link	c.139G>A	p.Ala47Thr	missense_variant	Exon 1 of 7	1		ENSP00000381102.4	Q86T03-2
PIP4P1	ENST00000557041.1 link	n.215G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000559

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000229

AC:

AN:

13088

Hom.:

AF XY:

0.000289

AC XY:

AN XY:

6916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000783

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000635

AC:

704

AN:

1109214

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

333

AN XY:

525172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000191

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000304

Gnomad4 NFE exome

AF:

0.000731

Gnomad4 OTH exome

AF:

0.000470

GnomAD4 genome

AF:

0.000302

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000326

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.000213

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139G>A (p.A47T) alteration is located in exon 1 (coding exon 1) of the TMEM55B gene. This alteration results from a G to A substitution at nucleotide position 139, causing the alanine (A) at amino acid position 47 to be replaced by a threonine (T). 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

0.079

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.12

N;N

REVEL

Benign

0.065

Sift

Benign

0.13

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.013

B;B

Vest4

0.19

MVP

0.043

MPC

0.58

ClinPred

0.11

GERP RS

3.5

Varity_R

0.16

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over