8-81680732-G-A

Position:

• chr8-81680732-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005536.4(IMPA1):​c.115C>T​(p.Pro39Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,610,958 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (24 hom.)
• Consequence: IMPA1 NM_005536.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.17

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009062231).
• BP6: Variant 8-81680732-G-A is Benign according to our data. Variant chr8-81680732-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPA1	NM_005536.4	c.115C>T	p.Pro39Ser	missense_variant	3/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.292C>T	p.Pro98Ser	missense_variant	4/10		NP_001138350.1
IMPA1	NM_001144879.2	c.115C>T	p.Pro39Ser	missense_variant	3/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.115C>T	p.Pro39Ser	missense_variant	3/9	1	NM_005536.4	ENSP00000256108	P1

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00287 AC: 721 AN: 251086 Hom.: 1 AF XY: 0.00300 AC XY: 407 AN XY: 135718

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00477 AC: 6956 AN: 1458718 Hom.: 24 Cov.: 28 AF XY: 0.00470 AC XY: 3410 AN XY: 725954

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00267

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00566

Gnomad4 OTH exome AF: 0.00478

GnomAD4 genome AF: 0.00288 AC: 438 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74450

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00506

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00401 Hom.: 0

Bravo AF: 0.00317

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00285 AC: 346

EpiCase AF: 0.00463

EpiControl AF: 0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	IMPA1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.60
DEOGEN2	Benign	0.27	T;.;.;T;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0091	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.72	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;N
REVEL	Benign	0.074
Sift	Benign	0.57	T;T;T;T;T;T;T
Sift4G	Benign	0.75	T;T;T;.;.;.;.
Polyphen		0.0040	B;.;.;.;.;.;.
Vest4		0.27
MVP		0.70
MPC		0.12
ClinPred		0.015	T
GERP RS		4.7
Varity_R		0.37
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs61755740; hg19: chr8-82592967; COSMIC: COSV56273272;