rs1556424100

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND5	unassigned_transcript_4815	c.61A>G	p.Thr21Ala	missense_variant	Exon 1 of 1
TRNL2	unassigned_transcript_4814	c.*61A>G		downstream_gene_variant
TRNH	unassigned_transcript_4812	c.*191A>G		downstream_gene_variant
TRNS2	unassigned_transcript_4813	c.*132A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.61A>G	p.Thr21Ala	missense_variant	Exon 1 of 1	6		ENSP00000354813.2
MT-TH	ENST00000387441.1	n.*191A>G		downstream_gene_variant		6
MT-TS2	ENST00000387449.1	n.*132A>G		downstream_gene_variant		6
MT-TL2	ENST00000387456.1	n.*61A>G		downstream_gene_variant		6

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

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.12397A>G (YP_003024036.1:p.Thr21Ala) variant in MTND5 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Autosomal recessive early-onset Parkinson disease 6 Other:1

Sep 01, 2008

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;