Variant 1-6235907-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012405.4(ICMT):c.5C>A(p.Ala2Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000583 in 1,114,480 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

ICMT
NM_012405.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

Variant links:

Genes affected

ICMT (HGNC:5350): (isoprenylcysteine carboxyl methyltransferase) This gene encodes the third of three enzymes that posttranslationally modify isoprenylated C-terminal cysteine residues in certain proteins and target those proteins to the cell membrane. This enzyme localizes to the endoplasmic reticulum. Alternative splicing may result in other transcript variants, but the biological validity of those transcripts has not been determined. [provided by RefSeq, Jul 2008]

ICMT links:

ICMT-DT (HGNC:28620): (ICMT divergent transcript)

ICMT-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21571702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICMT	NM_012405.4 linkuse as main transcript	c.5C>A	p.Ala2Glu	missense_variant	1/5	ENST00000343813.10
ICMT	XM_047416592.1 linkuse as main transcript	c.5C>A	p.Ala2Glu	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ICMT	ENST00000343813.10 linkuse as main transcript	c.5C>A	p.Ala2Glu	missense_variant	1/5	1	NM_012405.4	P1
ICMT	ENST00000489498.5 linkuse as main transcript	c.5C>A	p.Ala2Glu	missense_variant, NMD_transcript_variant	1/6	1
ICMT-DT	ENST00000650463.1 linkuse as main transcript	n.372+844G>T		intron_variant, non_coding_transcript_variant
ICMT	ENST00000474756.1 linkuse as main transcript	c.5C>A	p.Ala2Glu	missense_variant, NMD_transcript_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

146162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000256

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:

0.0000454

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000630

AC:

AN:

968318

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

455640

show subpopulations

Gnomad4 AFR exome

AF:

0.0000525

Gnomad4 AMR exome

AF:

0.00

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:

0.0000695

Gnomad4 OTH exome

AF:

0.0000281

GnomAD4 genome

AF:

0.0000274

AC:

AN:

146162

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71380

show subpopulations

Gnomad4 AFR

AF:

0.0000256

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:

0.0000454

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

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

Jan 03, 2024

The c.5C>A (p.A2E) alteration is located in exon 1 (coding exon 1) of the ICMT gene. This alteration results from a C to A substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a glutamic acid (E). 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

0.13

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.058

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.59

REVEL

Benign

0.063

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.040

Vest4

0.32

MutPred

0.28

Gain of solvent accessibility (P = 0.0456);

MVP

0.23

MPC

1.2

ClinPred

0.44

GERP RS

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.45

gMVP

0.79

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

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