Genetic Variant PIP5K1C:p.Ala661GlyfsTer81 (chr19-3633461-C-CG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_012398.3(PIP5K1C):c.1979dupC(p.Ala661GlyfsTer81) variant causes a frameshift change. The variant allele was found at a frequency of 0.000351 in 1,501,830 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

PIP5K1C
NM_012398.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.39

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.014 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP5K1C	NM_012398.3 link	c.1979dupC	p.Ala661GlyfsTer81	frameshift_variant	Exon 17 of 18	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.1979dupC	p.Ala661GlyfsTer81	frameshift_variant	Exon 17 of 18	1	NM_012398.3	ENSP00000335333.3		O60331-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000294

AC:

AN:

156664

AF XY:

0.000319

show subpopulations

Gnomad AFR exome

AF:

0.000161

Gnomad AMR exome

AF:

0.000257

Gnomad ASJ exome

AF:

0.000585

Gnomad EAS exome

AF:

0.0000748

Gnomad FIN exome

AF:

0.000136

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00144

GnomAD4 exome

AF:

0.000357

AC:

482

AN:

1349628

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

227

AN XY:

661000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000999

AC:

AN:

30036

Gnomad4 AMR exome

AF:

0.000388

AC:

AN:

30954

Gnomad4 ASJ exome

AF:

0.000100

AC:

AN:

19902

Gnomad4 EAS exome

AF:

0.0000798

AC:

AN:

37612

Gnomad4 SAS exome

AF:

0.000294

AC:

AN:

68074

Gnomad4 FIN exome

AF:

0.000375

AC:

AN:

48056

Gnomad4 NFE exome

AF:

0.000372

AC:

392

AN:

1054478

Gnomad4 Remaining exome

AF:

0.000470

AC:

AN:

55300

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<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:

0.000296

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000265

AC:

0.000264869

AN:

0.000264869

Gnomad4 AMR

AF:

0.000916

AC:

0.000915631

AN:

0.000915631

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000189

AC:

0.000188573

AN:

0.000188573

Gnomad4 NFE

AF:

0.000250

AC:

0.000250059

AN:

0.000250059

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000218

Hom.:

Bravo

AF:

0.000314

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 07, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 8 amino acid(s) are replaced with 80 different amino acid(s); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=13/187

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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