chr19-3633475-C-T

Position:

• chr19-3633475-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012398.3(PIP5K1C):​c.1966G>A​(p.Ala656Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00872 in 1,511,384 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (95 hom.)
• Consequence: PIP5K1C NM_012398.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.473

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037704706).
• BP6: Variant 19-3633475-C-T is Benign according to our data. Variant chr19-3633475-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 716239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00889 (12086/1359312) while in subpopulation MID AF= 0.0245 (124/5064). AF 95% confidence interval is 0.021. There are 95 homozygotes in gnomad4_exome. There are 6129 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIP5K1C	NM_012398.3	c.1966G>A	p.Ala656Thr	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.1966G>A	p.Ala656Thr	missense_variant	17/18	1	NM_012398.3	ENSP00000335333	P3
PIP5K1C	ENST00000679885.1	c.2044G>A	p.Ala682Thr	missense_variant	18/19			ENSP00000504894	A1
PIP5K1C	ENST00000539785.5	c.1921-306G>A		intron_variant		2		ENSP00000445992	A1
PIP5K1C	ENST00000679828.1	c.*1505G>A		3_prime_UTR_variant, NMD_transcript_variant	18/19			ENSP00000506175

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1080 AN: 151956 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00975

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00934

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00727 AC: 1297 AN: 178282 Hom.: 6 AF XY: 0.00794 AC XY: 763 AN XY: 96146

Gnomad AFR exome AF: 0.00564

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.000266

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00894

GnomAD4 exome AF: 0.00889 AC: 12086 AN: 1359312 Hom.: 95 Cov.: 31 AF XY: 0.00919 AC XY: 6129 AN XY: 666944

Gnomad4 AFR exome AF: 0.00760

Gnomad4 AMR exome AF: 0.00359

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.00207

Gnomad4 NFE exome AF: 0.00915

Gnomad4 OTH exome AF: 0.00974

GnomAD4 genome AF: 0.00715 AC: 1088 AN: 152072 Hom.: 7 Cov.: 33 AF XY: 0.00659 AC XY: 490 AN XY: 74352

Gnomad4 AFR AF: 0.00576

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00955

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00934

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00921 Hom.: 6

Bravo AF: 0.00743

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0118 AC: 101

ExAC AF: 0.00757 AC: 912

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PIP5K1C: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.0
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.044
Sift	Benign	0.65	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.23
MPC		0.31
ClinPred		0.021	T
GERP RS		-6.2
Varity_R		0.027

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35014191; hg19: chr19-3633473;