Genetic Variant PIP4P1:p.Arg260Trp (chr14-20458615-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_144568.4(PIP4P1):c.778C>T(p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

PIP4P1
NM_144568.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP4P1	NM_144568.4 link	c.778C>T	p.Arg260Trp	missense_variant	Exon 7 of 7	ENST00000250489.9	NP_653169.2	Q86T03-1
PIP4P1	NM_001100814.3 link	c.799C>T	p.Arg267Trp	missense_variant	Exon 7 of 7		NP_001094284.1	Q86T03-2
PIP4P1	XM_024449739.2 link	c.693C>T	p.Ala231Ala	synonymous_variant	Exon 6 of 6		XP_024305507.1
PIP4P1	XM_024449740.2 link	c.672C>T	p.Ala224Ala	synonymous_variant	Exon 6 of 6		XP_024305508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIP4P1	ENST00000250489.9 link	c.778C>T	p.Arg260Trp	missense_variant	Exon 7 of 7	1	NM_144568.4	ENSP00000250489.4		Q86T03-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152142

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:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251026

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000494

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000306

AC:

448

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

216

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000388

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.799C>T (p.R267W) alteration is located in exon 7 (coding exon 7) of the TMEM55B gene. This alteration results from a C to T substitution at nucleotide position 799, causing the arginine (R) at amino acid position 267 to be replaced by a tryptophan (W). 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

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.15

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.81

MVP

0.35

MPC

1.6

ClinPred

0.85

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.88

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