chr19-3633466-G-A

Position:

• chr19-3633466-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012398.3(PIP5K1C):​c.1975C>T​(p.Pro659Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00604 in 1,508,592 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (35 hom.)
• Consequence: PIP5K1C NM_012398.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006764978).
• BP6: Variant 19-3633466-G-A is Benign according to our data. Variant chr19-3633466-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-3633466-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIP5K1C	NM_012398.3	c.1975C>T	p.Pro659Ser	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	c.1975C>T	p.Pro659Ser	missense_variant	17/18	1	NM_012398.3	ENSP00000335333	P3
PIP5K1C	ENST00000679885.1	c.2053C>T	p.Pro685Ser	missense_variant	18/19			ENSP00000504894	A1
PIP5K1C	ENST00000539785.5	c.1921-297C>T		intron_variant		2		ENSP00000445992	A1
PIP5K1C	ENST00000679828.1	c.*1514C>T		3_prime_UTR_variant, NMD_transcript_variant	18/19			ENSP00000506175

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00676

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00302 AC: 523 AN: 173244 Hom.: 2 AF XY: 0.00308 AC XY: 287 AN XY: 93238

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000602

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00631 AC: 8557 AN: 1356256 Hom.: 35 Cov.: 31 AF XY: 0.00605 AC XY: 4023 AN XY: 664562

Gnomad4 AFR exome AF: 0.000928

Gnomad4 AMR exome AF: 0.000482

Gnomad4 ASJ exome AF: 0.0000496

Gnomad4 EAS exome AF: 0.000185

Gnomad4 SAS exome AF: 0.0000145

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.00776

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00336 AC XY: 250 AN XY: 74500

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00676

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00555 Hom.: 4

Bravo AF: 0.00346

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00293 AC: 353

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PIP5K1C: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.031
Sift	Benign	0.12	T
Sift4G	Benign	0.27	T
Polyphen		0.010	B
Vest4		0.33
MVP		0.14
MPC		0.33
ClinPred		0.0080	T
GERP RS		2.8
Varity_R		0.058

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

Other links and lift over

dbSNP: rs34633286; hg19: chr19-3633464; COSMIC: COSV100096397; COSMIC: COSV100096397;