8-81676257-T-C

Position:

chr8-81676257-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005536.4(IMPA1):c.325A>G(p.Ile109Val) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,349,110 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 32)

Exomes 𝑓: 0.012 ( 144 hom. )

Consequence

IMPA1
NM_005536.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011817932).

BP6

Variant 8-81676257-T-C is Benign according to our data. Variant chr8-81676257-T-C is described in ClinVar as [Benign]. Clinvar id is 3341538.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1820/152178) while in subpopulation NFE AF= 0.0196 (1332/67976). AF 95% confidence interval is 0.0187. There are 19 homozygotes in gnomad4. There are 813 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IMPA1	NM_005536.4 linkuse as main transcript	c.325A>G	p.Ile109Val	missense_variant	5/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2 linkuse as main transcript	c.502A>G	p.Ile168Val	missense_variant	6/10		NP_001138350.1
IMPA1	NM_001144879.2 linkuse as main transcript	c.325A>G	p.Ile109Val	missense_variant	5/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10 linkuse as main transcript	c.325A>G	p.Ile109Val	missense_variant	5/9	1	NM_005536.4	ENSP00000256108	P1	P29218-1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1823

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.00717

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.0119

AC:

2253

AN:

188574

Hom.:

AF XY:

0.0127

AC XY:

1312

AN XY:

103540

show subpopulations

Gnomad AFR exome

AF:

0.00317

Gnomad AMR exome

AF:

0.00552

Gnomad ASJ exome

AF:

0.00389

Gnomad EAS exome

AF:

0.000846

Gnomad SAS exome

AF:

0.0142

Gnomad FIN exome

AF:

0.00798

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0122

AC:

14643

AN:

1196932

Hom.:

144

Cov.:

AF XY:

0.0124

AC XY:

7451

AN XY:

599984

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.00506

Gnomad4 ASJ exome

AF:

0.00355

Gnomad4 EAS exome

AF:

0.00346

Gnomad4 SAS exome

AF:

0.0123

Gnomad4 FIN exome

AF:

0.00801

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.0120

AC:

1820

AN:

152178

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

813

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.00824

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00717

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.0159

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00548

AC:

ESP6500EA

AF:

0.0170

AC:

145

ExAC

AF:

0.0129

AC:

1560

Asia WGS

AF:

0.00781

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

IMPA1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.;T;T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;D;T;T;T;D;D

MetaRNN

Benign

0.012

T;T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

L;L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.71

N;N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.22

T;T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;.;.;.;.

Polyphen

0.11

B;.;.;.;.;.;.

Vest4

0.23

MPC

0.13

ClinPred

0.015

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over