8-81680745-C-T

Position:

• chr8-81680745-C-T

Variant summary

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

The NM_005536.4(IMPA1):​c.102G>A​(p.Met34Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IMPA1 NM_005536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

Genes affected

IMPA1 (HGNC:6050): (inositol monophosphatase 1) This gene encodes an enzyme that dephosphorylates myo-inositol monophosphate to generate free myo-inositol, a precursor of phosphatidylinositol, and is therefore an important modulator of intracellular signal transduction via the production of the second messengers myoinositol 1,4,5-trisphosphate and diacylglycerol. This enzyme can also use myo-inositol-1,3-diphosphate, myo-inositol-1,4-diphosphate, scyllo-inositol-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates. This enzyme shows magnesium-dependent phosphatase activity and is inhibited by therapeutic concentrations of lithium. Inhibition of inositol monophosphate hydroylosis and subsequent depletion of inositol for phosphatidylinositol synthesis may explain the anti-manic and anti-depressive effects of lithium administered to treat bipolar disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. A pseudogene of this gene is also present on chromosome 8q21.13. [provided by RefSeq, Dec 2014]

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
IMPA1	NM_005536.4	c.102G>A	p.Met34Ile	missense_variant	3/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.279G>A	p.Met93Ile	missense_variant	4/10		NP_001138350.1
IMPA1	NM_001144879.2	c.102G>A	p.Met34Ile	missense_variant	3/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.102G>A	p.Met34Ile	missense_variant	3/9	1	NM_005536.4	ENSP00000256108	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Jun 05, 2024

The c.279G>A (p.M93I) alteration is located in exon 4 (coding exon 3) of the IMPA1 gene. This alteration results from a G to A substitution at nucleotide position 279, causing the methionine (M) at amino acid position 93 to be replaced by an isoleucine (I). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.;T;T;T;.
Eigen	Benign	0.044
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.51	T;T;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.15	T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;.;.;.;.
Polyphen		0.17	B;.;.;.;.;.;.
Vest4		0.66
MutPred		0.46		Loss of ubiquitination at K36 (P = 0.054);Loss of ubiquitination at K36 (P = 0.054);.;.;Loss of ubiquitination at K36 (P = 0.054);.;Loss of ubiquitination at K36 (P = 0.054);
MVP		0.68
MPC		0.13
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.81
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-82592980;