19-3633461-CGG-CG

Variant names:

• chr19-3633461-CG-C
• rs748532409
• NM_012398.3:c.1979delC

Variant summary

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

The NM_012398.3(PIP5K1C):​c.1979delC​(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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012398.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	NM_012398.3	MANE Select	c.1979delC	p.Pro660ArgfsTer225	frameshift	Exon 17 of 18	NP_036530.1	O60331-1
	PIP5K1C	NM_001195733.2		c.1921-293delC		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1979delC	p.Pro660ArgfsTer225	frameshift	Exon 17 of 18	ENSP00000335333.3	O60331-1
	PIP5K1C	ENST00000876625.1		c.2096delC	p.Pro699ArgfsTer225	frameshift	Exon 18 of 19	ENSP00000546684.1
	PIP5K1C	ENST00000967141.1		c.2081delC	p.Pro694ArgfsTer225	frameshift	Exon 17 of 18	ENSP00000637200.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000511 AC: 80 AN: 156664 AF XY: 0.000508

Gnomad AFR exome AF: 0.000964

Gnomad AMR exome AF: 0.000359

Gnomad ASJ exome AF: 0.000585

Gnomad EAS exome AF: 0.000374

Gnomad FIN exome AF: 0.000679

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.00115

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000433 AC: 13 AN: 30008

American (AMR) AF: 0.000356 AC: 11 AN: 30882

Ashkenazi Jewish (ASJ) AF: 0.000352 AC: 7 AN: 19866

East Asian (EAS) AF: 0.000106 AC: 4 AN: 37560

South Asian (SAS) AF: 0.000413 AC: 28 AN: 67854

European-Finnish (FIN) AF: 0.000376 AC: 18 AN: 47934

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5208

European-Non Finnish (NFE) AF: 0.000104 AC: 110 AN: 1053660

Other (OTH) AF: 0.000235 AC: 13 AN: 55240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00135 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=20/180	disease causing

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

Other links and lift over

dbSNP: rs748532409; hg19: chr19-3633459; COSMIC: COSV58950216; COSMIC: COSV58950216;