rs2268432

Variant names:

• chr8-81674542-G-T
• rs2268432
• NM_005536.4:c.349-593C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

IMPA1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 59

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
IMPA1	NM_005536.4	c.349-593C>A		intron_variant	Intron 5 of 8	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.526-593C>A		intron_variant	Intron 6 of 9		NP_001138350.1
IMPA1	NM_001144879.2	c.349-593C>A		intron_variant	Intron 5 of 7		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.349-593C>A		intron_variant	Intron 5 of 8	1	NM_005536.4	ENSP00000256108.5

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

African (AFR) AF: 0.0232 AC: 44 AN: 1898

American (AMR) AF: 0.156 AC: 546 AN: 3510

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 219 AN: 2216

East Asian (EAS) AF: 0.603 AC: 1716 AN: 2846

South Asian (SAS) AF: 0.104 AC: 2110 AN: 20208

European-Finnish (FIN) AF: 0.212 AC: 1193 AN: 5630

Middle Eastern (MID) AF: 0.0971 AC: 34 AN: 350

European-Non Finnish (NFE) AF: 0.139 AC: 8160 AN: 58752

Other (OTH) AF: 0.148 AC: 758 AN: 5118

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

African (AFR) AF: 0.0267 AC: 1109 AN: 41570

American (AMR) AF: 0.129 AC: 1973 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.571 AC: 2950 AN: 5162

South Asian (SAS) AF: 0.112 AC: 538 AN: 4818

European-Finnish (FIN) AF: 0.219 AC: 2313 AN: 10564

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9594 AN: 67988

Other (OTH) AF: 0.114 AC: 240 AN: 2108

Alfa AF: 0.128 Hom.: 220

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
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs2268432; hg19: chr8-82586777;