7-30755585-T-A

Position:

• chr7-30755585-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006774.5(INMT):​c.526T>A​(p.Tyr176Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INMT NM_006774.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45

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 (HGNC:):

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INMT	NM_006774.5	c.526T>A	p.Tyr176Asn	missense_variant	3/3	ENST00000013222.5	NP_006765.4
INMT	NM_001199219.2	c.523T>A	p.Tyr175Asn	missense_variant	3/3		NP_001186148.1
INMT-MINDY4	NR_037598.1	n.375+1647T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INMT	ENST00000013222.5	c.526T>A	p.Tyr176Asn	missense_variant	3/3	1	NM_006774.5	ENSP00000013222.5
INMT-MINDY4	ENST00000458257.5	n.359+1647T>A		intron_variant		2		ENSP00000456039.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.526T>A (p.Y176N) alteration is located in exon 3 (coding exon 3) of the INMT gene. This alteration results from a T to A substitution at nucleotide position 526, causing the tyrosine (Y) at amino acid position 176 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.3	D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.84		Loss of stability (P = 0.0738);.;
MVP		0.32
MPC		0.91
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.98
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-30795201;