8-81680737-C-T

Position:

chr8-81680737-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000256108.10(IMPA1):c.110G>A(p.Ser37Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

IMPA1
ENST00000256108.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2711841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IMPA1	NM_005536.4 linkuse as main transcript	c.110G>A	p.Ser37Asn	missense_variant	3/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2 linkuse as main transcript	c.287G>A	p.Ser96Asn	missense_variant	4/10		NP_001138350.1
IMPA1	NM_001144879.2 linkuse as main transcript	c.110G>A	p.Ser37Asn	missense_variant	3/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10 linkuse as main transcript	c.110G>A	p.Ser37Asn	missense_variant	3/9	1	NM_005536.4	ENSP00000256108	P1	P29218-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251076

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458454

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725804

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.287G>A (p.S96N) alteration is located in exon 4 (coding exon 3) of the IMPA1 gene. This alteration results from a G to A substitution at nucleotide position 287, causing the serine (S) at amino acid position 96 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.051

MetaRNN

Benign

0.27

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

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.7

M;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.19

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.041

D;T;T;.;.;.;.

Polyphen

0.90

P;.;.;.;.;.;.

Vest4

0.61

MVP

0.82

MPC

0.38

ClinPred

0.24

GERP RS

4.7

Varity_R

0.91

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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