rs1011521364

Variant names:

• chr10-58267605-T-C
• rs1011521364
• NM_152230.5:c.7A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152230.5(IPMK):​c.7A>G​(p.Thr3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000627 in 1,596,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IPMK NM_152230.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.311
• Publications: 0 publications found

Genes affected

IPMK (HGNC:20739): (inositol polyphosphate multikinase) This gene encodes a member of the inositol phosphokinase family. The encoded protein has 3-kinase, 5-kinase and 6-kinase activities on phosphorylated inositol substrates. The encoded protein plays an important role in the biosynthesis of inositol 1,3,4,5,6-pentakisphosphate, and has a preferred 5-kinase activity. This gene may play a role in nuclear mRNA export. Pseudogenes of this gene are located on the long arm of chromosome 13 and the short arm of chromosome 19. [provided by RefSeq, Dec 2010]

IPMK Gene-Disease associations (from GenCC):

• hereditary neuroendocrine tumor of small intestine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043477803).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPMK	NM_152230.5	c.7A>G	p.Thr3Ala	missense_variant	Exon 1 of 6	ENST00000373935.4	NP_689416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPMK	ENST00000373935.4	c.7A>G	p.Thr3Ala	missense_variant	Exon 1 of 6	1	NM_152230.5	ENSP00000363046.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152032 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444070 Hom.: 0 Cov.: 31 AF XY: 0.00000697 AC XY: 5 AN XY: 717286

African (AFR) AF: 0.0000302 AC: 1 AN: 33108

American (AMR) AF: 0.00 AC: 0 AN: 42674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38972

South Asian (SAS) AF: 0.00 AC: 0 AN: 84640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103464

Other (OTH) AF: 0.00 AC: 0 AN: 59544

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152032 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7A>G (p.T3A) alteration is located in exon 1 (coding exon 1) of the IPMK gene. This alteration results from a A to G substitution at nucleotide position 7, causing the threonine (T) at amino acid position 3 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	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.31
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.021
Sift	Benign	0.51	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.13		Loss of glycosylation at T3 (P = 0.0057);
MVP		0.014
MPC		0.14
ClinPred		0.021	T
GERP RS		0.78
Varity_R		0.074
gMVP		0.21
Mutation Taster		=94/6	polymorphism

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: rs1011521364; hg19: chr10-60027365;