chr7-30752287-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_006774.5(INMT):c.137A>C(p.His46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,613,830 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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: 𝑓 0.0063 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 74 hom. )

Consequence

INMT
NM_006774.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.964

Publications

19 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071540475).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00784 (11458/1461580) while in subpopulation EAS AF = 0.0205 (815/39698). AF 95% confidence interval is 0.0194. There are 74 homozygotes in GnomAdExome4. There are 5627 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INMT	NM_006774.5 link	c.137A>C	p.His46Pro	missense_variant	Exon 1 of 3	ENST00000013222.5	NP_006765.4	O95050-1
INMT	NM_001199219.2 link	c.137A>C	p.His46Pro	missense_variant	Exon 1 of 3		NP_001186148.1	O95050-2
INMT-MINDY4	NR_037598.1 link	n.153A>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.137A>C	p.His46Pro	missense_variant	Exon 1 of 3	1	NM_006774.5	ENSP00000013222.5		O95050-1
INMT-MINDY4	ENST00000458257.5 link	n.137A>C		non_coding_transcript_exon_variant	Exon 1 of 20	2		ENSP00000456039.1		F8WBC2

Frequencies

GnomAD3 genomes

AF:

0.00633

AC:

963

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00882

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00758

AC:

1905

AN:

251386

AF XY:

0.00786

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.0183

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.00820

Gnomad OTH exome

AF:

0.00652

GnomAD4 exome

AF:

0.00784

AC:

11458

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

5627

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33476

American (AMR)

AF:

0.00159

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00949

AC:

248

AN:

26126

East Asian (EAS)

AF:

0.0205

AC:

815

AN:

39698

South Asian (SAS)

AF:

0.00348

AC:

300

AN:

86254

European-Finnish (FIN)

AF:

0.0148

AC:

789

AN:

53386

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00791

AC:

8799

AN:

1111780

Other (OTH)

AF:

0.00651

AC:

393

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

616

1233

1849

2466

3082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00633

AC:

963

AN:

152250

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

491

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41548

American (AMR)

AF:

0.00170

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3470

East Asian (EAS)

AF:

0.0141

AC:

AN:

5172

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00881

AC:

599

AN:

67992

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00775

Hom.:

Bravo

AF:

0.00490

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00824

AC:

1000

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00646

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

0.0017

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0072

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

-0.96

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.19

Sift

Benign

0.17

T;T

Sift4G

Benign

0.20

T;T

Polyphen

1.0

D;.

Vest4

0.39

MVP

0.35

MPC

0.86

ClinPred

0.047

GERP RS

1.8

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.71

gMVP

0.56

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over