chr7-30752203-G-C

Position:

• chr7-30752203-G-C

Variant summary

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

The NM_006774.5(INMT):​c.53G>C​(p.Arg18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: INMT NM_006774.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252

Genes affected

INMT (HGNC:6069): (indolethylamine N-methyltransferase) N-methylation of endogenous and xenobiotic compounds is a major method by which they are degraded. This gene encodes an enzyme that N-methylates indoles such as tryptamine. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream MINDY4 (aka FAM188B) gene. In rodents and other mammals such as cetartiodactyla this gene is in the opposite orientation compared to its orientation in human and other primates and this gene appears to have been lost in carnivora and chiroptera. [provided by RefSeq, Jul 2019]

INMT-MINDY4 (HGNC:41995): (INMT-MINDY4 readthrough (NMD candidate)) This locus represents rare but naturally occurring read-through transcription between the INMT (indolethylamine N-methyltransferase) and FAM188B (family with sequence similarity 188, member B) genes on chromosome 7. The read-through transcript is unlikely to produce a protein because it is a nonsense-mediated mRNA decay (NMD) candidate based on translation from the supported INMT start codon. [provided by RefSeq, Nov 2010]

INMT (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=0.25166258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INMT	NM_006774.5	c.53G>C	p.Arg18Thr	missense_variant	1/3	ENST00000013222.5	NP_006765.4
INMT	NM_001199219.2	c.53G>C	p.Arg18Thr	missense_variant	1/3		NP_001186148.1
INMT-MINDY4	NR_037598.1	n.69G>C		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5	c.53G>C	p.Arg18Thr	missense_variant	1/3	1	NM_006774.5	ENSP00000013222.5
INMT-MINDY4	ENST00000458257.5	n.53G>C		non_coding_transcript_exon_variant	1/20	2		ENSP00000456039.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 19, 2024

The c.53G>C (p.R18T) alteration is located in exon 1 (coding exon 1) of the INMT gene. This alteration results from a G to C substitution at nucleotide position 53, causing the arginine (R) at amino acid position 18 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.093
Sift	Benign	0.16	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.15	B;.
Vest4		0.42
MutPred		0.60		Gain of glycosylation at R18 (P = 0.1323);Gain of glycosylation at R18 (P = 0.1323);
MVP		0.14
MPC		0.25
ClinPred		0.23	T
GERP RS		0.035
Varity_R		0.19
gMVP		0.11

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: rs1786099656; hg19: chr7-30791819;