rs863224084

Positions:

• chr5-140645661-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002488.5(NDUFA2):​c.225del​(p.Asn76MetfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NDUFA2 NM_002488.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 0.209

Genes affected

NDUFA2 (HGNC:7685): (NADH:ubiquinone oxidoreductase subunit A2) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

TMCO6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140645661-TC-T is Pathogenic according to our data. Variant chr5-140645661-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214712.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA2	NM_002488.5	c.225del	p.Asn76MetfsTer4	frameshift_variant	3/3	ENST00000252102.9	NP_002479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA2	ENST00000252102.9	c.225del	p.Asn76MetfsTer4	frameshift_variant	3/3	1	NM_002488.5	ENSP00000252102	P1
NDUFA2	ENST00000512088.1	c.*41del		3_prime_UTR_variant	3/3	2		ENSP00000427220
NDUFA2	ENST00000502960.1	n.533del		non_coding_transcript_exon_variant	2/2	2
NDUFA2	ENST00000510680.1	n.59+1594del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in abnormal protein length as the last 24 amino acids are replaced with 3 different amino acids; This variant is associated with the following publications: (PMID: 27159321, 32154054, 28857146, 33233646, 32304865) -

Cystic Leukoencephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

MyeliNeuroGene Lab, McGill University Health Center Research Institute

-

This is the first report of autosomal recessive mutations in NDUFA2 associated with cystic leukoencephalopathy. -

Mitochondrial complex 1 deficiency, nuclear type 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224084; hg19: chr5-140025246;