1-6225106-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_012405.4(ICMT):c.829A>G(p.Ile277Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,782 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 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
ICMT
NM_012405.4 missense
NM_012405.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 7.42
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]
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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=0.3266812).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ICMT | NM_012405.4 | c.829A>G | p.Ile277Val | missense_variant | 5/5 | ENST00000343813.10 | |
ICMT | XM_011541140.3 | c.541A>G | p.Ile181Val | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ICMT | ENST00000343813.10 | c.829A>G | p.Ile277Val | missense_variant | 5/5 | 1 | NM_012405.4 | P1 | |
ICMT | ENST00000489498.5 | c.*585A>G | 3_prime_UTR_variant, NMD_transcript_variant | 6/6 | 1 | ||||
ICMT | ENST00000474756.1 | c.*374A>G | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251034Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135678
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461556Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727078
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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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 | Mar 31, 2023 | The c.829A>G (p.I277V) alteration is located in exon 5 (coding exon 5) of the ICMT gene. This alteration results from a A to G substitution at nucleotide position 829, causing the isoleucine (I) at amino acid position 277 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at