NM_014222.3:c.140G>A

Variant names:

• chr9-122152320-C-T
• rs1346883008
• NM_014222.3:c.140G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_014222.3(NDUFA8):​c.140G>A​(p.Arg47His) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,882 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NDUFA8 NM_014222.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62
• Publications: 0 publications found

Genes affected

NDUFA8 (HGNC:7692): (NADH:ubiquinone oxidoreductase subunit A8) The protein encoded by this gene belongs to the complex I 19 kDa subunit family. Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays an important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

NDUFA8 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 37

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-122152321-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1064534.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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: 0.48122 (below the threshold of 3.09). Trascript score misZ: 0.71331 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 37.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014222.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA8	NM_014222.3	MANE Select	c.140G>A	p.Arg47His	missense	Exon 2 of 4	NP_055037.1	P51970
	NDUFA8	NM_001318195.2		c.140G>A	p.Arg47His	missense	Exon 2 of 4	NP_001305124.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA8	ENST00000373768.4	TSL:1 MANE Select	c.140G>A	p.Arg47His	missense	Exon 2 of 4	ENSP00000362873.3	P51970
	NDUFA8	ENST00000942086.1		c.131G>A	p.Arg44His	missense	Exon 2 of 4	ENSP00000612145.1
	NDUFA8	ENST00000886470.1		c.52-4047G>A		intron	N/A	ENSP00000556529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251434 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461882 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.021	D
Sift4G	Benign	0.063	T
Polyphen		0.20	B
Vest4		0.87
MutPred		0.64		Gain of catalytic residue at R47 (P = 0.0572)
MVP		0.95
MPC		0.39
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.67
gMVP		0.73
Mutation Taster		=23/77	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: rs1346883008; hg19: chr9-124914599;