9-68923342-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003558.4(PIP5K1B):c.1157G>C(p.Arg386Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIP5K1B NM_003558.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89

Genes affected

PIP5K1B (HGNC:8995): (phosphatidylinositol-4-phosphate 5-kinase type 1 beta) Predicted to enable 1-phosphatidylinositol-4-phosphate 5-kinase activity. Predicted to be involved in regulation of phosphatidylinositol 3-kinase signaling. Predicted to act upstream of or within phosphatidylinositol biosynthetic process. Located in uropod. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIP5K1B	NM_003558.4	c.1157G>C	p.Arg386Thr	missense_variant	12/16	ENST00000265382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIP5K1B	ENST00000265382.8	c.1157G>C	p.Arg386Thr	missense_variant	12/16	1	NM_003558.4	P1
PIP5K1B	ENST00000478500.3	c.1277G>C	p.Arg426Thr	missense_variant, NMD_transcript_variant	13/21	1
PIP5K1B	ENST00000541509.5	c.1157G>C	p.Arg386Thr	missense_variant	11/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.1157G>C (p.R386T) alteration is located in exon 12 (coding exon 9) of the PIP5K1B gene. This alteration results from a G to C substitution at nucleotide position 1157, causing the arginine (R) at amino acid position 386 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.8	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.94		Loss of MoRF binding (P = 0.0275);Loss of MoRF binding (P = 0.0275);
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.97

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: rs1826507240; hg19: chr9-71538258; COSMIC: COSV105036566;