8-81659413-A-C

Position:

• chr8-81659413-A-C

Variant summary

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

The NM_005536.4(IMPA1):​c.772T>G​(p.Leu258Val) 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. 14/21 in silico tools predict a benign outcome for this variant. 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: 0.143

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.103138775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPA1	NM_005536.4	c.772T>G	p.Leu258Val	missense_variant	9/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.949T>G	p.Leu317Val	missense_variant	10/10		NP_001138350.1
IMPA1	NM_001144879.2	c.*66T>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.772T>G	p.Leu258Val	missense_variant	9/9	1	NM_005536.4	ENSP00000256108.5
IMPA1	ENST00000449740.6	c.949T>G	p.Leu317Val	missense_variant	10/10	1		ENSP00000408526.2
IMPA1	ENST00000311489	c.*66T>G		3_prime_UTR_variant	8/8	2		ENSP00000311803.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

Sep 02, 2024

The c.949T>G (p.L317V) alteration is located in exon 10 (coding exon 9) of the IMPA1 gene. This alteration results from a T to G substitution at nucleotide position 949, causing the leucine (L) at amino acid position 317 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.051
Sift	Benign	0.094	T;D
Sift4G	Benign	0.11	T;T
Polyphen		0.0060	B;.
Vest4		0.045
MutPred		0.70		Gain of MoRF binding (P = 0.0811);.;
MVP		0.085
MPC		0.13
ClinPred		0.099	T
GERP RS		-2.1
Varity_R		0.12
gMVP		0.56

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: rs1806600513; hg19: chr8-82571648;