rs1058401

Variant names:

• chr8-81658396-C-T
• rs1058401
• NM_005536.4:c.*955G>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.*955G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,028 control chromosomes in the GnomAD database, including 8,922 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 0.33 (8921 hom., cov: 33)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: IMPA1 NM_005536.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005536.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA1	NM_005536.4	MANE Select	c.*955G>A		3_prime_UTR	Exon 9 of 9	NP_005527.1
	IMPA1	NM_001144878.2		c.*955G>A		3_prime_UTR	Exon 10 of 10	NP_001138350.1
	IMPA1	NM_001144879.2		c.*1083G>A		3_prime_UTR	Exon 8 of 8	NP_001138351.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA1	ENST00000256108.10	TSL:1 MANE Select	c.*955G>A		3_prime_UTR	Exon 9 of 9	ENSP00000256108.5

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50356 AN: 151902 Hom.: 8898 Cov.: 33

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.500 AC: 4 AN: 8 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 4 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 4 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.332 AC: 50430 AN: 152020 Hom.: 8921 Cov.: 33 AF XY: 0.335 AC XY: 24912 AN XY: 74304

African (AFR) AF: 0.351 AC: 14566 AN: 41452

American (AMR) AF: 0.272 AC: 4152 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3470

East Asian (EAS) AF: 0.719 AC: 3722 AN: 5174

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4822

European-Finnish (FIN) AF: 0.413 AC: 4353 AN: 10540

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20298 AN: 67960

Other (OTH) AF: 0.320 AC: 676 AN: 2114

Alfa AF: 0.308 Hom.: 10465

Bravo AF: 0.328

Asia WGS AF: 0.459 AC: 1593 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.065
DANN	Benign	0.32
PhyloP100		-2.2
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: rs1058401; hg19: chr8-82570631;