chr22-42086237-TTC-T

Position:

• chr22-42086237-TTC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002490.6(NDUFA6):​c.331_332del​(p.Glu111SerfsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NDUFA6 NM_002490.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.20

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.145 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-42086237-TTC-T is Pathogenic according to our data. Variant chr22-42086237-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 487475.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA6	NM_002490.6	c.331_332del	p.Glu111SerfsTer35	frameshift_variant	3/3	ENST00000498737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA6	ENST00000498737.8	c.331_332del	p.Glu111SerfsTer35	frameshift_variant	3/3	1	NM_002490.6	P1
NDUFA6	ENST00000617763.1	c.409_410del	p.Glu137SerfsTer35	frameshift_variant	3/3	1
NDUFA6	ENST00000470753.1	c.160_161del	p.Glu54SerfsTer35	frameshift_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

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: rs1569463838; hg19: chr22-42482241;