chr6-33722877-C-G

Position:

• chr6-33722877-C-G

Variant summary

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

The NM_054111.5(IP6K3):​c.1076G>C​(p.Gly359Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IP6K3 NM_054111.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078207254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IP6K3	NM_054111.5	c.1076G>C	p.Gly359Ala	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.1076G>C	p.Gly359Ala	missense_variant	6/6	1	NM_054111.5	ENSP00000293756	P1
IP6K3	ENST00000451316.6	c.1076G>C	p.Gly359Ala	missense_variant	7/7	2		ENSP00000398861	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 27, 2024

The c.1076G>C (p.G359A) alteration is located in exon 7 (coding exon 5) of the IP6K3 gene. This alteration results from a G to C substitution at nucleotide position 1076, causing the glycine (G) at amino acid position 359 to be replaced by an alanine (A). 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	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.0
DANN	Benign	0.65
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.58	.;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.070
Sift	Benign	0.27	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0030	B;B
Vest4		0.095
MutPred		0.23		Loss of catalytic residue at G359 (P = 0.0939);Loss of catalytic residue at G359 (P = 0.0939);
MVP		0.21
MPC		0.21
ClinPred		0.052	T
GERP RS		1.1
Varity_R		0.051
gMVP		0.16

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: rs1235206103; hg19: chr6-33690654;