rs193302928

Variant names:

• chrM-10321-T-C
• rs193302928
• ENST00000361227.2:c.263T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000361227.2(MT-ND3):​c.263T>C​(p.Val88Ala) 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V88I) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0085 (AC: 522)
• Consequence: MT-ND3 ENST00000361227.2 missense
• Scores: Apogee2 Benign 0.038
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 No linked disesase in Mitomap
• Conservation: PhyloP100: 2.69
• Publications: 5 publications found

Genes affected

MT-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4L (HGNC:7460): (mitochondrially encoded NADH 4L dehydrogenase) Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy and diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)

TRNR Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.038404237 < 0.5 .
• BP6: Variant M-10321-T-C is Benign according to our data. Variant chrM-10321-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0085
• BS2: High AC in GnomadMitoHomoplasmic at 1070

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND3	unassigned_transcript_4808	c.263T>C	p.Val88Ala	missense_variant	Exon 1 of 1
ND4L	unassigned_transcript_4810	c.-149T>C		upstream_gene_variant
TRNR	unassigned_transcript_4809	c.-84T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND3	ENST00000361227.2	c.263T>C	p.Val88Ala	missense_variant	Exon 1 of 1	6		ENSP00000355206.2
MT-ND4L	ENST00000361335.1	c.-149T>C		upstream_gene_variant		6		ENSP00000354728.1
MT-TR	ENST00000387439.1	n.-84T>C		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0085 AC: 522

Gnomad homoplasmic AF: 0.019 AC: 1070 AN: 56424

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56424

Alfa AF: 0.0116 Hom.: 531

Mitomap

No disease associated.

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 12, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.10321T>C (YP_003024033.1:p.Val88Ala) variant in MTND3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.038
Hmtvar	Benign	0.090
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
DEOGEN2	Benign	0.35	T
LIST_S2	Benign	0.40	T
MutationAssessor	Benign	0.38	N
PhyloP100		2.7
PROVEAN	Benign	-2.0	N
Sift	Uncertain	0.027	D
Sift4G	Benign	0.14	T
GERP RS		3.1
Varity_R		0.14

Other links and lift over

dbSNP: rs193302928; hg19: chrM-10322;