chr7-30755480-T-A

Variant names:

• chr7-30755480-T-A
• rs778230606
• NM_006774.5:c.421T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006774.5(INMT):​c.421T>A​(p.Cys141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. C141R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INMT NM_006774.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INMT	NM_006774.5	c.421T>A	p.Cys141Ser	missense_variant	Exon 3 of 3	ENST00000013222.5	NP_006765.4
INMT	NM_001199219.2	c.418T>A	p.Cys140Ser	missense_variant	Exon 3 of 3		NP_001186148.1
INMT-MINDY4	NR_037598.1	n.375+1542T>A		intron_variant	Intron 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5	c.421T>A	p.Cys141Ser	missense_variant	Exon 3 of 3	1	NM_006774.5	ENSP00000013222.5
INMT-MINDY4	ENST00000458257.5	n.359+1542T>A		intron_variant	Intron 2 of 19	2		ENSP00000456039.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	0.16
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.5	D;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.80		Loss of methylation at K140 (P = 0.0142);.;
MVP		0.56
MPC		0.77
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.91
gMVP		0.72
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs778230606; hg19: chr7-30795096;