chr6-33723040-G-C

Position:

• chr6-33723040-G-C

Variant summary

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

The NM_054111.5(IP6K3):​c.913C>G​(p.Gln305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IP6K3 NM_054111.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

Genes affected

IP6K3 (HGNC:17269): (inositol hexakisphosphate kinase 3) This gene encodes a protein that belongs to the inositol phosphokinase (IPK) family. This protein is likely responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). It may also convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IP6K3	NM_054111.5	c.913C>G	p.Gln305Glu	missense_variant	6/6	ENST00000293756.5	NP_473452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IP6K3	ENST00000293756.5	c.913C>G	p.Gln305Glu	missense_variant	6/6	1	NM_054111.5	ENSP00000293756	P1
IP6K3	ENST00000451316.6	c.913C>G	p.Gln305Glu	missense_variant	7/7	2		ENSP00000398861	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Sep 13, 2023

The c.913C>G (p.Q305E) alteration is located in exon 7 (coding exon 5) of the IP6K3 gene. This alteration results from a C to G substitution at nucleotide position 913, causing the glutamine (Q) at amino acid position 305 to be replaced by a glutamic acid (E). 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	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.0061	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.069
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.63	P;P
Vest4		0.21
MutPred		0.69		Loss of MoRF binding (P = 0.0542);Loss of MoRF binding (P = 0.0542);
MVP		0.36
MPC		0.39
ClinPred		0.47	T
GERP RS		5.0
Varity_R		0.22
gMVP		0.28

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: rs758519226; hg19: chr6-33690817;