M-4316-A-G

Position:

• chrM-4316-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000387365.1(MT-TI):​n.54A>G variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.00050 (AC: 30)
• Consequence: MT-TI ENST00000387365.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 11
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1 HCM-with-hearing-loss-/-poss.-hypertension-factor
• Conservation: PhyloP100: 6.88

Genes affected

MT-TI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI (HGNC:):

MT-TQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant M-4316-A-G is Benign according to our data. Variant chrM-4316-A-G is described in ClinVar as [Benign]. Clinvar id is 235014.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 22

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNI	TRNI.1	n.54A>G		non_coding_transcript_exon_variant	1/1
TRNQ	TRNQ.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TI	ENST00000387365.1	n.54A>G		non_coding_transcript_exon_variant	1/1
MT-TQ	ENST00000387372.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.00050 AC: 30

Gnomad homoplasmic AF: 0.00039 AC: 22 AN: 56429

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56429

Mitomap

HCM-with-hearing-loss-/-poss.-hypertension-factor

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 06, 2011

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MTTI m.A4316G This is a novel variant that has not been reported in the literature. The affected region is thought to be involved in tRNA folding and tertiary structure stabilization of tRNA-Ile. Other mutations affecting tRNA structure have been implicated in cardiomyopathy (Ito et al 1992, Degoul et al 1998). Conservation analysis indicates that Adenosine is highly conserved at position 4316 with more than 95% of all mammals maintaining Adenosine at this location. A variant at the neighboring nucleotide (4317) has been identified in an individual with MELAS and a fatal infantile cardiomyopathy (Tanaka et al 1990, Ito et al 1992, Degoul et al 1998). However the 4317 was also found in 3 out of 6391 presumably healthy individuals. Mitochondrial variants, when associated with disease, are often associated with extensive variable expressivity. Thus, with the currently available data on mitochondrial mutations in general and the m.A4316G variant in the MTTI gene in particular, the contribution of this variant to this patient’s HCM cannot be determined. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Benign:1

Benign, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Jul 12, 2019

The NC_012920.1:m.4316A>G variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876661360; hg19: chrM-4317;