M-12397-A-G

Variant names:

• chrM-12397-A-G
• rs1556424100
• ENST00000361567.2:c.61A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BS1 BS2

The ENST00000361567.2(MT-ND5):​c.61A>G​(p.Thr21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0062 (AC: 378)
• Consequence: MT-ND5 ENST00000361567.2 missense
• Scores: Apogee2 Benign 0.012
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1 PD+-early-onset
• Conservation: PhyloP100: -7.13
• Publications: 1 publications found

Genes affected

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.012341363 < 0.5 .
• BP6: Variant M-12397-A-G is Benign according to our data. Variant chrM-12397-A-G is described in ClinVar as Benign. ClinVar VariationId is 9705.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: High frequency in mitomap database: 0.0062
• BS2: High AC in GnomadMitoHomoplasmic at 186

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361567.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ND5	ENST00000361567.2	TSL:6	c.61A>G	p.Thr21Ala	missense	Exon 1 of 1	ENSP00000354813.2	P03915
	MT-TH	ENST00000387441.1	TSL:6	n.*191A>G		downstream_gene	N/A
	MT-TS2	ENST00000387449.1	TSL:6	n.*132A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0062 AC: 378

Gnomad homoplasmic AF: 0.0033 AC: 186 AN: 56432

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56432

Alfa AF: 0.00265 Hom.: 121

Mitomap

Disease(s): PD+-early-onset

Status: Reported

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	-	Autosomal recessive early-onset Parkinson disease 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.012
Hmtvar	Benign	0.26
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
DEOGEN2	Benign	0.014	T
LIST_S2	Benign	0.33	T
MutationAssessor	Benign	0.10	N
PhyloP100		-7.1
PROVEAN	Benign	-0.74	N
Sift4G	Benign	0.23	T
GERP RS		-9.1
Varity_R		0.18
Mutation Taster		=94/6	polymorphism

Other links and lift over

dbSNP: rs1556424100; hg19: chrM-12398;