chr6-33722856-C-A

Variant names:

• chr6-33722856-C-A
• rs748608668
• NM_054111.5:c.1097G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_054111.5(IP6K3):​c.1097G>T​(p.Arg366Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IP6K3 NM_054111.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054111.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IP6K3	NM_054111.5	MANE Select	c.1097G>T	p.Arg366Leu	missense	Exon 6 of 6	NP_473452.2	Q5TAQ4
	IP6K3	NM_001142883.2		c.1097G>T	p.Arg366Leu	missense	Exon 7 of 7	NP_001136355.1	Q96PC2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IP6K3	ENST00000293756.5	TSL:1 MANE Select	c.1097G>T	p.Arg366Leu	missense	Exon 6 of 6	ENSP00000293756.4	Q96PC2
	IP6K3	ENST00000451316.6	TSL:2	c.1097G>T	p.Arg366Leu	missense	Exon 7 of 7	ENSP00000398861.1	Q96PC2
	IP6K3	ENST00000885829.1		c.1097G>T	p.Arg366Leu	missense	Exon 6 of 6	ENSP00000555888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111658

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.66		Loss of MoRF binding (P = 0.0617)
MVP		0.70
MPC		0.84
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.81
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs748608668; hg19: chr6-33690633; COSMIC: COSV53390850;