rs752054300

Variant names:

• chr9-122148266-C-A
• rs752054300
• NM_014222.3:c.227G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-122148266-C-A
• chr9-122148266-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014222.3(NDUFA8):​c.227G>T​(p.Arg76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFA8 NM_014222.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210
• 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: Uncertain_significance. The variant received 1 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: 0.48122 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09413862).

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.227G>T	p.Arg76Leu	missense	Exon 3 of 4	NP_055037.1	P51970
	NDUFA8	NM_001318195.2		c.227G>T	p.Arg76Leu	missense	Exon 3 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.227G>T	p.Arg76Leu	missense	Exon 3 of 4	ENSP00000362873.3	P51970
	NDUFA8	ENST00000942086.1		c.218G>T	p.Arg73Leu	missense	Exon 3 of 4	ENSP00000612145.1
	NDUFA8	ENST00000886470.1		c.59G>T	p.Arg20Leu	missense	Exon 2 of 3	ENSP00000556529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.43		Loss of MoRF binding (P = 0.0575)
MVP		0.67
MPC		0.37
ClinPred		0.24	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.42
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752054300; hg19: chr9-124910545;