Genetic Variant PIP5K1C:p.Arg691Leu (chr19-3637462-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001300849.2(PIP5K1C):c.2072G>T(p.Arg691Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,535,674 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 31)

Exomes 𝑓: 0.00065 ( 10 hom. )

Consequence

PIP5K1C
NM_001300849.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.187

Variant links:

Genes affected

PIP5K1C (HGNC:8996): (phosphatidylinositol-4-phosphate 5-kinase type 1 gamma) This locus encodes a type I phosphatidylinositol 4-phosphate 5-kinase. The encoded protein catalyzes phosphorylation of phosphatidylinositol 4-phosphate, producing phosphatidylinositol 4,5-bisphosphate. This enzyme is found at synapses and has been found to play roles in endocytosis and cell migration. Mutations at this locus have been associated with lethal congenital contractural syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Sep 2010]

PIP5K1C links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036550164).

BP6

Variant 19-3637462-C-A is Benign according to our data. Variant chr19-3637462-C-A is described in ClinVar as [Benign]. Clinvar id is 3059157.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00121 (184/152284) while in subpopulation EAS AF= 0.0252 (130/5160). AF 95% confidence interval is 0.0217. There are 3 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP5K1C	NM_012398.3 link	c.1920+1422G>T		intron_variant	Intron 16 of 17	ENST00000335312.8	NP_036530.1	O60331-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIP5K1C	ENST00000335312.8 link	c.1920+1422G>T		intron_variant	Intron 16 of 17	1	NM_012398.3	ENSP00000335333.3		O60331-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0247

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00238

AC:

316

AN:

132824

Hom.:

AF XY:

0.00224

AC XY:

162

AN XY:

72426

show subpopulations

Gnomad AFR exome

AF:

0.000787

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0283

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000389

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.000651

AC:

901

AN:

1383390

Hom.:

Cov.:

AF XY:

0.000620

AC XY:

423

AN XY:

682616

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0209

Gnomad4 SAS exome

AF:

0.000341

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00143

GnomAD4 genome

AF:

0.00121

AC:

184

AN:

152284

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0252

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.00152

ExAC

AF:

0.000757

AC:

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PIP5K1C-related disorder

Benign:1

Jun 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.58

DANN

Benign

0.89

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0037

Polyphen

0.0

Vest4

0.16

MVP

0.043

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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