Variant chr19-3633444-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_012398.3(PIP5K1C):c.1997G>A(p.Ser666Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,497,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PIP5K1C
NM_012398.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity PI51C_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.109078944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIP5K1C	NM_012398.3 linkuse as main transcript	c.1997G>A	p.Ser666Asn	missense_variant	17/18	ENST00000335312.8	NP_036530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIP5K1C	ENST00000335312.8 linkuse as main transcript	c.1997G>A	p.Ser666Asn	missense_variant	17/18	1	NM_012398.3	ENSP00000335333	P3	O60331-1
PIP5K1C	ENST00000679885.1 linkuse as main transcript	c.2075G>A	p.Ser692Asn	missense_variant	18/19			ENSP00000504894	A1
PIP5K1C	ENST00000539785.5 linkuse as main transcript	c.1921-275G>A		intron_variant		2		ENSP00000445992	A1	O60331-4
PIP5K1C	ENST00000679828.1 linkuse as main transcript	c.*1536G>A		3_prime_UTR_variant, NMD_transcript_variant	18/19			ENSP00000506175

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

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:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000491

AC:

AN:

162928

Hom.:

AF XY:

0.0000798

AC XY:

AN XY:

87772

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:

0.000394

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.000272

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1345660

Hom.:

Cov.:

AF XY:

0.0000532

AC XY:

AN XY:

658106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000950

Gnomad4 OTH exome

AF:

0.0000181

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74464

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:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.1997G>A (p.S666N) alteration is located in exon 17 (coding exon 17) of the PIP5K1C gene. This alteration results from a G to A substitution at nucleotide position 1997, causing the serine (S) at amino acid position 666 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.055

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.65

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Benign

0.13

Polyphen

0.42

Vest4

0.48

MutPred

0.10

Loss of phosphorylation at S666 (P = 0.0157);

MVP

0.44

MPC

0.46

ClinPred

0.20

GERP RS

3.4

Varity_R

0.37

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