chr8-81659399-T-C

Position:

• chr8-81659399-T-C

Variant summary

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

The NM_005536.4(IMPA1):​c.786A>G​(p.Ile262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IMPA1 NM_005536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

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.786A>G	p.Ile262Met	missense_variant	9/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.963A>G	p.Ile321Met	missense_variant	10/10		NP_001138350.1
IMPA1	NM_001144879.2	c.*80A>G		3_prime_UTR_variant	8/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.786A>G	p.Ile262Met	missense_variant	9/9	1	NM_005536.4	ENSP00000256108.5
IMPA1	ENST00000449740.6	c.963A>G	p.Ile321Met	missense_variant	10/10	1		ENSP00000408526.2
IMPA1	ENST00000311489	c.*80A>G		3_prime_UTR_variant	8/8	2		ENSP00000311803.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Oct 28, 2024

The c.963A>G (p.I321M) alteration is located in exon 10 (coding exon 9) of the IMPA1 gene. This alteration results from a A to G substitution at nucleotide position 963, causing the isoleucine (I) at amino acid position 321 to be replaced by a methionine (M). 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	0.19
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.017	D;T
Sift4G	Uncertain	0.025	D;T
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.64		Gain of MoRF binding (P = 0.0814);.;
MVP		0.74
MPC		0.53
ClinPred		0.87	D
GERP RS		0.62
Varity_R		0.57
gMVP		0.79

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: chr8-82571634;