rs763006208

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_002490.6(NDUFA6):c.309delT(p.Met104CysfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

NDUFA6
NM_002490.6 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: -0.533

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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 0.202 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 22-42086260-TA-T is Pathogenic according to our data. Variant chr22-42086260-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549665.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA6	NM_002490.6 link	c.309delT	p.Met104CysfsTer35	frameshift_variant	Exon 3 of 3	ENST00000498737.8	NP_002481.3	P56556A0A2Y9D025

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFA6	ENST00000498737.8 link	c.309delT	p.Met104CysfsTer35	frameshift_variant	Exon 3 of 3	1	NM_002490.6	ENSP00000418842.3	P56556
NDUFA6	ENST00000617763.1 link	c.387delT	p.Met130CysfsTer35	frameshift_variant	Exon 3 of 3	1		ENSP00000482543.1	A0A2Y9D025
NDUFA6	ENST00000470753.1 link	c.138delT	p.Met47CysfsTer35	frameshift_variant	Exon 2 of 2	2		ENSP00000473478.1	R4GN43

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251488

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135922

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727238

show subpopulations

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:

0.0000980

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000112

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000907

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 33

Pathogenic:1

Dec 13, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Jan 20, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.387delT (p.M130Cfs*35) alteration, located in exon 3 (coding exon 3) of the NDUFA6 gene, consists of a deletion of one nucleotide at position 387, causing a translational frameshift with a predicted alternate stop codon after 35 amino acids. This alteration occurs at the 3' terminus of the NDUFA6 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 15% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.387delT allele has an overall frequency of 0.01% (16/282896) total alleles studied. The highest observed frequency was 0.01% (16/129192) of European (non-Finnish) alleles. This variant, designated as 309del was confirmed in trans with a second NDUFA6 frameshift variant in an infant presenting with unusual movements suggestive of seizure disorder, elevated blood gas lactate, abnormal brain MRI with white matter changes, and deterioration as a result of status epilepticus, apnea episodes, and persistent lactic acidosis (Alston, 2018). Based on the available evidence, this alteration is classified as likely pathogenic. -

Mitochondrial disease

Pathogenic:1

Jul 19, 2018

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NDUFA6-related disorder

Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NDUFA6 c.387delT variant is predicted to result in a frameshift and premature protein termination (p.Met130Cysfs*35). This variant , also designated c.309del (p.Met104Cysfs*35) in an alternate transcript, has been reported in compound heterozygous states individuals with mitochondrial complex I deficiency (Alston et al. 2018. PubMed ID: 30245030; Table S3, French et al. 2022. PubMed ID: 35586607). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NDUFA6 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over