M-10172-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The ENST00000361227.2(MT-ND3):c.114G>A(p.Glu38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0078 (AC: 476)
• Consequence: MT-ND3 ENST00000361227.2 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 0.721

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP6: Variant M-10172-G-A is Benign according to our data. Variant chrM-10172-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1328510.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.721 with no splicing effect.
• BS1: High frequency in mitomap database: 0.0078
• BS2: High AC in GnomadMitoHomoplasmic at 328

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND3	ENST00000361227.2	c.114G>A	p.Glu38=	synonymous_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0078 AC: 476

Gnomad homoplasmic AF: 0.0058 AC: 328 AN: 56420

Gnomad heteroplasmic AF: 0.00014 AC: 8 AN: 56420

Alfa AF: 0.00672 Hom.: 55

Mitomap

No disease associated.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 26, 2021

The m.10172G>A (p.E38E) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in over 0.8% of individuals in the GenBank dataset (BS1), including in haplogroups J2b (97.91% of individuals), U6a (7.44% of individuals), Q1f (10/17 individuals), and M13b (7/13 individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 0.58% including in haplogroup J at 6.7%. If an affected individual is not a member of one of these haplogroups, further evaluation of the variant in that particular individual should be considered. This is a synonymous variant (BP7). In summary, this variant meets criteria to be classified as likely benign given its synonymous nature and high frequency in the general population. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP7. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879100790; hg19: chrM-10173;