rs77743549

Positions:

• chr7-30752287-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000013222.5(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. 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 ENST00000013222.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.964

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071540475).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome 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 gnomad4_exome. There are 5627 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INMT	NM_006774.5	c.137A>C	p.His46Pro	missense_variant	1/3	ENST00000013222.5	NP_006765.4
INMT-MINDY4	NR_037598.1	n.153A>C		non_coding_transcript_exon_variant	1/20
INMT	NM_001199219.2	c.137A>C	p.His46Pro	missense_variant	1/3		NP_001186148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5	c.137A>C	p.His46Pro	missense_variant	1/3	1	NM_006774.5	ENSP00000013222	P4
INMT	ENST00000409539.1	c.137A>C	p.His46Pro	missense_variant	1/3	1		ENSP00000386961	A1
INMT	ENST00000484180.1	n.301-1444A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 963 AN: 152132 Hom.: 10 Cov.: 32

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

GnomAD3 exomes AF: 0.00758 AC: 1905 AN: 251386 Hom.: 10 AF XY: 0.00786 AC XY: 1068 AN XY: 135882

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 SAS exome AF: 0.00356

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.: 74 Cov.: 33 AF XY: 0.00774 AC XY: 5627 AN XY: 727134

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.00348

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.00791

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00633 AC: 963 AN: 152250 Hom.: 10 Cov.: 32 AF XY: 0.00660 AC XY: 491 AN XY: 74448

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00807 Hom.: 11

Bravo AF: 0.00490

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00824 AC: 1000

Asia WGS AF: 0.00664 AC: 23 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	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	0.0017
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.39	T
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	T
GERP RS		1.8
Varity_R		0.71
gMVP		0.56

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: rs77743549; hg19: chr7-30791903; COSMIC: COSV50002901;