7-30755459-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006774.5(INMT):​c.400G>A​(p.Ala134Thr) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Consequence

INMT
NM_006774.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.196
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-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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.035667956).
BP6
Variant 7-30755459-G-A is Benign according to our data. Variant chr7-30755459-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2323025.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
INMTNM_006774.5 linkuse as main transcriptc.400G>A p.Ala134Thr missense_variant 3/3 ENST00000013222.5 NP_006765.4 O95050-1
INMTNM_001199219.2 linkuse as main transcriptc.397G>A p.Ala133Thr missense_variant 3/3 NP_001186148.1 O95050-2
INMT-MINDY4NR_037598.1 linkuse as main transcriptn.375+1521G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
INMTENST00000013222.5 linkuse as main transcriptc.400G>A p.Ala134Thr missense_variant 3/31 NM_006774.5 ENSP00000013222.5 O95050-1
INMT-MINDY4ENST00000458257.5 linkuse as main transcriptn.359+1521G>A intron_variant 2 ENSP00000456039.1 F8WBC2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
0.014
DANN
Benign
0.74
DEOGEN2
Benign
0.0089
T;.
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0074
N
LIST_S2
Benign
0.12
T;T
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.036
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-0.55
N;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
1.5
N;N
REVEL
Benign
0.081
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0010
B;.
Vest4
0.038
MutPred
0.42
Gain of phosphorylation at A134 (P = 0.0767);.;
MVP
0.17
MPC
0.16
ClinPred
0.083
T
GERP RS
-7.1
Varity_R
0.077
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1786209390; hg19: chr7-30795075; API