dbSNP rs915: IMPA1:c.*1196G>A (chr8-81658155-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005536.4(IMPA1):c.*1196G>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 0.401 in 151,852 control chromosomes in the GnomAD database, including 12,717 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 0.40 ( 12717 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

IMPA1
NM_005536.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.19

Publications

13 publications found

Variant links:

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

IMPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
IMPA1	NM_005536.4 link	c.*1196G>A	3_prime_UTR_variant	Exon 9 of 9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2 link	c.*1196G>A	3_prime_UTR_variant	Exon 10 of 10		NP_001138350.1
IMPA1	NM_001144879.2 link	c.*1324G>A	3_prime_UTR_variant	Exon 8 of 8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10 link	c.*1196G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_005536.4	ENSP00000256108.5

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60752

AN:

151736

Hom.:

12689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.469

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.407

Gnomad EAS

AF:

0.720

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.378

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.401

AC:

60840

AN:

151852

Hom.:

12717

Cov.:

AF XY:

0.402

AC XY:

29840

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.471

AC:

19522

AN:

41414

American (AMR)

AF:

0.326

AC:

4967

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

1413

AN:

3468

East Asian (EAS)

AF:

0.720

AC:

3723

AN:

5170

South Asian (SAS)

AF:

0.316

AC:

1523

AN:

4820

European-Finnish (FIN)

AF:

0.431

AC:

4527

AN:

10510

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.351

AC:

23808

AN:

67922

Other (OTH)

AF:

0.380

AC:

802

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1817

3633

5450

7266

9083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.386

Hom.:

2551

Bravo

AF:

0.402

Asia WGS

AF:

0.489

AC:

1700

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.098

(source)

DANN

Benign

0.58

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over