19-3633466-G-T

Variant names:

• chr19-3633466-G-T
• rs34633286
• NM_012398.3:c.1975C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012398.3(PIP5K1C):​c.1975C>A​(p.Pro659Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P659S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIP5K1C NM_012398.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12221432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIP5K1C	NM_012398.3	c.1975C>A	p.Pro659Thr	missense_variant	Exon 17 of 18	ENST00000335312.8	NP_036530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIP5K1C	ENST00000335312.8	c.1975C>A	p.Pro659Thr	missense_variant	Exon 17 of 18	1	NM_012398.3	ENSP00000335333.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.15	T
Sift4G	Benign	0.26	T
Polyphen		0.023	B
Vest4		0.37
MutPred		0.22		Loss of catalytic residue at P659 (P = 0.0357);
MVP		0.15
MPC		0.37
ClinPred		0.43	T
GERP RS		2.8
Varity_R		0.077

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

Other links and lift over

dbSNP: rs34633286; hg19: chr19-3633464;