7-30753916-G-A

Position:

• chr7-30753916-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006774.5(INMT):​c.340G>A​(p.Ala114Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00217 in 1,614,004 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: INMT NM_006774.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.22

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00923565).
• BP6: Variant 7-30753916-G-A is Benign according to our data. Variant chr7-30753916-G-A is described in ClinVar as [Benign]. Clinvar id is 783491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1626/152288) while in subpopulation AFR AF= 0.0371 (1540/41544). AF 95% confidence interval is 0.0355. There are 25 homozygotes in gnomad4. There are 775 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INMT	NM_006774.5	c.340G>A	p.Ala114Thr	missense_variant	2/3	ENST00000013222.5	NP_006765.4
INMT	NM_001199219.2	c.337G>A	p.Ala113Thr	missense_variant	2/3		NP_001186148.1
INMT-MINDY4	NR_037598.1	n.353G>A		non_coding_transcript_exon_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5	c.340G>A	p.Ala114Thr	missense_variant	2/3	1	NM_006774.5	ENSP00000013222.5
INMT-MINDY4	ENST00000458257.5	n.337G>A		non_coding_transcript_exon_variant	2/20	2		ENSP00000456039.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152170 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00305 AC: 765 AN: 250816 Hom.: 20 AF XY: 0.00217 AC XY: 294 AN XY: 135650

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00128 AC: 1869 AN: 1461716 Hom.: 41 Cov.: 32 AF XY: 0.00113 AC XY: 822 AN XY: 727156

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152288 Hom.: 25 Cov.: 32 AF XY: 0.0104 AC XY: 775 AN XY: 74466

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00197 Hom.: 12

Bravo AF: 0.0130

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00383 AC: 465

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.098
Sift	Benign	0.049	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.80	P;.
Vest4		0.37
MVP		0.13
MPC		0.35
ClinPred		0.023	T
GERP RS		3.0
Varity_R		0.24
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76338133; hg19: chr7-30793532;