chr22-42087124-C-G

Position:

• chr22-42087124-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000498737.8(NDUFA6):​c.191G>C​(p.Arg64Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFA6 ENST00000498737.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.65

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 22-42087124-C-G is Pathogenic according to our data. Variant chr22-42087124-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 487477.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA6	NM_002490.6	c.191G>C	p.Arg64Pro	missense_variant	2/3	ENST00000498737.8	NP_002481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA6	ENST00000498737.8	c.191G>C	p.Arg64Pro	missense_variant	2/3	1	NM_002490.6	ENSP00000418842	P1
NDUFA6	ENST00000617763.1	c.269G>C	p.Arg90Pro	missense_variant	2/3	1		ENSP00000482543
NDUFA6	ENST00000470753.1	c.20G>C	p.Arg7Pro	missense_variant	1/2	2		ENSP00000473478

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 33 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 13, 2018

- -

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Jul 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.0040	.;D;D
Vest4		0.94, 0.96
MutPred		0.89		.;Loss of MoRF binding (P = 5e-04);.;
MVP		0.97
MPC		0.96
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs750830935; hg19: chr22-42483128;