chr19-3633461-CG-C

Position:

• chr19-3633461-CG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_012398.3(PIP5K1C):​c.1979del​(p.Pro660ArgfsTer225) variant causes a frameshift change. The variant allele was found at a frequency of 0.000152 in 1,348,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PIP5K1C NM_012398.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIP5K1C	NM_012398.3	c.1979del	p.Pro660ArgfsTer225	frameshift_variant	17/18	ENST00000335312.8	NP_036530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIP5K1C	ENST00000335312.8	c.1979del	p.Pro660ArgfsTer225	frameshift_variant	17/18	1	NM_012398.3	ENSP00000335333	P3
PIP5K1C	ENST00000679885.1	c.2057del	p.Pro686ArgfsTer225	frameshift_variant	18/19			ENSP00000504894	A1
PIP5K1C	ENST00000539785.5	c.1921-293del		intron_variant		2		ENSP00000445992	A1
PIP5K1C	ENST00000679828.1	c.*1518del		3_prime_UTR_variant, NMD_transcript_variant	18/19			ENSP00000506175

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.000152 AC: 205 AN: 1348212 Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 116 AN XY: 660260

Gnomad4 AFR exome AF: 0.000433

Gnomad4 AMR exome AF: 0.000356

Gnomad4 ASJ exome AF: 0.000352

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.000413

Gnomad4 FIN exome AF: 0.000376

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome Cov.: 33

Alfa AF: 0.00135 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2022

Frameshift variant predicted to result in protein truncation as the last 9 amino acids are replaced with 224 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs748532409; hg19: chr19-3633459;