chr22-42090719-G-C

Variant names:

• chr22-42090719-G-C
• rs1801311
• NM_002490.6:c.26C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002490.6(NDUFA6):​c.26C>G​(p.Ala9Gly) 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. 13/21 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. A9V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: NDUFA6 NM_002490.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.918
• Publications: 73 publications found

Genes affected

NDUFA6 (HGNC:7690): (NADH:ubiquinone oxidoreductase subunit A6) This gene encodes a member of the LYR family of proteins that contain a highly conserved tripeptide (LYR) motif near the N-terminus. The encoded protein is an accessory subunit of NADH: ubiquinone oxidorerductase (Complex I), which is the largest enzyme of the mitochondrial membrane respiratory chain. Complex I functions in electron transfer from NADH to the respiratory chain. [provided by RefSeq, Oct 2016]

NDUFA6-DT (HGNC:45273): (NDUFA6 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA6	NM_002490.6	c.26C>G	p.Ala9Gly	missense_variant	Exon 1 of 3	ENST00000498737.8	NP_002481.3
NDUFA6-DT	NR_034118.2	n.-214G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA6	ENST00000498737.8	c.26C>G	p.Ala9Gly	missense_variant	Exon 1 of 3	1	NM_002490.6	ENSP00000418842.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 30111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.89	T
PhyloP100		0.92
PrimateAI	Benign	0.34	T
REVEL	Benign	0.11
Sift4G	Benign	0.14	.;T
Vest4		0.14
MutPred		0.22		.;Gain of loop (P = 0.0312);
MVP		0.62
MPC		0.21
ClinPred		0.35	T
GERP RS		2.4
PromoterAI		0.0067	Neutral
Varity_R		0.036
gMVP		0.39
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 1

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

Other links and lift over

dbSNP: rs1801311; hg19: chr22-42486723;