Genetic Variant INMT:p.Glu43Gln (chr7-30752277-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006774.5(INMT):c.127G>C(p.Glu43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. E43K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INMT
NM_006774.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.632

Publications

0 publications found

Variant links:

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 links:

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-MINDY4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057308435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INMT	NM_006774.5 link	c.127G>C	p.Glu43Gln	missense_variant	Exon 1 of 3	ENST00000013222.5	NP_006765.4	O95050-1
INMT	NM_001199219.2 link	c.127G>C	p.Glu43Gln	missense_variant	Exon 1 of 3		NP_001186148.1	O95050-2
INMT-MINDY4	NR_037598.1 link	n.143G>C		non_coding_transcript_exon_variant	Exon 1 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5 link	c.127G>C	p.Glu43Gln	missense_variant	Exon 1 of 3	1	NM_006774.5	ENSP00000013222.5		O95050-1
INMT-MINDY4	ENST00000458257.5 link	n.127G>C		non_coding_transcript_exon_variant	Exon 1 of 20	2		ENSP00000456039.1		F8WBC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.5

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0070

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.66

N;N

PhyloP100

-0.63

PrimateAI

Benign

0.28

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.027

Sift

Benign

0.51

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.082

B;.

Vest4

0.048

MutPred

0.43

Loss of ubiquitination at K39 (P = 0.0992);Loss of ubiquitination at K39 (P = 0.0992);

MVP

0.20

MPC

0.17

ClinPred

0.041

GERP RS

2.1

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.26

gMVP

0.16

Mutation Taster

=91/9

polymorphism

(source)

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

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7-30752277-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over