8-81674542-G-T

Position:

• chr8-81674542-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005536.4(IMPA1):​c.349-593C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 252,688 control chromosomes in the GnomAD database, including 3,632 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (2065 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1567 hom.)
• Consequence: IMPA1 NM_005536.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPA1	NM_005536.4	c.349-593C>A		intron_variant		ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.526-593C>A		intron_variant			NP_001138350.1
IMPA1	NM_001144879.2	c.349-593C>A		intron_variant			NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.349-593C>A		intron_variant		1	NM_005536.4	ENSP00000256108	P1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19184 AN: 152042 Hom.: 2068 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.147 AC: 14780 AN: 100528 Hom.: 1567 Cov.: 0 AF XY: 0.143 AC XY: 7852 AN XY: 54952

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.0988

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.126 AC: 19180 AN: 152160 Hom.: 2065 Cov.: 32 AF XY: 0.131 AC XY: 9728 AN XY: 74366

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.114

Alfa AF: 0.132 Hom.: 219

Bravo AF: 0.121

Asia WGS AF: 0.291 AC: 1012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.43

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: rs2268432; hg19: chr8-82586777;