NM_014214.3:c.491A>T

Variant names:

• chr18-12028043-A-T
• rs1907930776
• NM_014214.3:c.491A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014214.3(IMPA2):​c.491A>T​(p.Asp164Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D164G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IMPA2 NM_014214.3 missense, splice_region
• Scores: Splicing: ADA: 0.01648
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.31
• Publications: 0 publications found

Genes affected

IMPA2 (HGNC:6051): (inositol monophosphatase 2) This locus encodes an inositol monophosphatase. The encoded protein catalyzes the dephosphoylration of inositol monophosphate and plays an important role in phosphatidylinositol signaling. This locus may be associated with susceptibility to bipolar disorder. [provided by RefSeq, Jan 2011]

ENSG00000293189 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA2	NM_014214.3	MANE Select	c.491A>T	p.Asp164Val	missense splice_region	Exon 6 of 8	NP_055029.1	O14732-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA2	ENST00000269159.8	TSL:1 MANE Select	c.491A>T	p.Asp164Val	missense splice_region	Exon 6 of 8	ENSP00000269159.3	O14732-1
	IMPA2	ENST00000588927.5	TSL:5	c.-77A>T		splice_region	Exon 6 of 8	ENSP00000464767.1	K7EII9
	IMPA2	ENST00000589238.5	TSL:3	c.-77A>T		splice_region	Exon 6 of 8	ENSP00000465416.1	K7EII9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451612 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102770

Other (OTH) AF: 0.00 AC: 0 AN: 60088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.0012
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		0.062	B
Vest4		0.67
MutPred		0.42		Gain of MoRF binding (P = 0.0338)
MVP		0.64
MPC		1.5
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.060		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: rs1907930776; hg19: chr18-12028042;