NM_002488.5:c.199G>T

Variant names:

• chr5-140647265-C-A
• rs1235620751
• NM_002488.5:c.199G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002488.5(NDUFA2):​c.199G>T​(p.Ala67Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A67A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NDUFA2 NM_002488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94
• Publications: 1 publications found

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]

IK (HGNC:5958): (IK cytokine) The protein encoded by this gene was identified by its RED repeat, a stretch of repeated arginine, glutamic acid and aspartic acid residues. The protein localizes to discrete dots within the nucleus, excluding the nucleolus. Its function is unknown. This gene maps to chromosome 5; however, a pseudogene may exist on chromosome 2. [provided by RefSeq, Jul 2008]

TMCO6 (HGNC:28814): (transmembrane and coiled-coil domains 6) Predicted to enable nuclear import signal receptor activity. Predicted to be involved in protein import into nucleus. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.24046 (below the threshold of 3.09). Trascript score misZ: -0.5731 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 13, Leigh syndrome, cystic leukoencephalopathy without megalencephaly, Leigh syndrome with leukodystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA2	NM_002488.5	c.199G>T	p.Ala67Ser	missense_variant	Exon 2 of 3	ENST00000252102.9	NP_002479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA2	ENST00000252102.9	c.199G>T	p.Ala67Ser	missense_variant	Exon 2 of 3	1	NM_002488.5	ENSP00000252102.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399576 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688902

African (AFR) AF: 0.00 AC: 0 AN: 31722

American (AMR) AF: 0.00 AC: 0 AN: 37108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39198

South Asian (SAS) AF: 0.00 AC: 0 AN: 75650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080334

Other (OTH) AF: 0.00 AC: 0 AN: 57580

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 13 Uncertain:1

Jun 11, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.0044	T
PhyloP100		6.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.98	D;.
Vest4		0.77
MutPred		0.86		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.50
MPC		1.1
ClinPred		0.99	D
GERP RS		5.9
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.75
gMVP		0.77
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1235620751; hg19: chr5-140026850;