1-6235857-C-A

Position:

• chr1-6235857-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012405.4(ICMT):​c.55G>T​(p.Ala19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,092,372 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ICMT NM_012405.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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-DT (HGNC:):

ACMG classification

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=0.13093695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ICMT	NM_012405.4	c.55G>T	p.Ala19Ser	missense_variant	1/5	ENST00000343813.10	NP_036537.1
ICMT	XM_047416592.1	c.55G>T	p.Ala19Ser	missense_variant	1/4		XP_047272548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ICMT	ENST00000343813.10	c.55G>T	p.Ala19Ser	missense_variant	1/5	1	NM_012405.4	ENSP00000343552.5
ICMT	ENST00000489498.5	n.55G>T		non_coding_transcript_exon_variant	1/6	1		ENSP00000466222.1
ICMT	ENST00000474756.1	n.55G>T		non_coding_transcript_exon_variant	1/4	2		ENSP00000467999.1
ICMT-DT	ENST00000650463.1	n.372+794C>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1092372 Hom.: 0 Cov.: 31 AF XY: 0.00000188 AC XY: 1 AN XY: 530822

Gnomad4 AFR exome AF: 0.00

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: 0.00000109

Gnomad4 OTH exome AF: 0.0000241

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2023

The c.55G>T (p.A19S) alteration is located in exon 1 (coding exon 1) of the ICMT gene. This alteration results from a G to T substitution at nucleotide position 55, causing the alanine (A) at amino acid position 19 to be replaced by a serine (S). 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	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.092
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.020	B
Vest4		0.096
MutPred		0.38		Loss of helix (P = 0.0072);
MVP		0.23
MPC		0.98
ClinPred		0.21	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.16

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: rs988984411; hg19: chr1-6295917;