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GeneBe

22-42086285-TTTAA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_002490.6(NDUFA6):c.281_284del(p.Ile94LysfsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

NDUFA6
NM_002490.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.40
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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 0.855 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 22-42086285-TTTAA-T is Pathogenic according to our data. Variant chr22-42086285-TTTAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1324784.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NDUFA6NM_002490.6 linkuse as main transcriptc.281_284del p.Ile94LysfsTer44 frameshift_variant 3/3 ENST00000498737.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDUFA6ENST00000498737.8 linkuse as main transcriptc.281_284del p.Ile94LysfsTer44 frameshift_variant 3/31 NM_002490.6 P1
NDUFA6ENST00000617763.1 linkuse as main transcriptc.359_362del p.Ile120LysfsTer44 frameshift_variant 3/31
NDUFA6ENST00000470753.1 linkuse as main transcriptc.110_113del p.Ile37LysfsTer44 frameshift_variant 2/22

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000328
AC:
5
AN:
152258
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000795
AC:
20
AN:
251474
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461858
Hom.:
0
AF XY:
0.0000591
AC XY:
43
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000674
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000328
AC:
5
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000680
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 18, 2022The c.359_362delTTAA (p.I120Kfs*44) alteration, located in exon 3 (coding exon 3) of the NDUFA6 gene, consists of a deletion of 4 nucleotides from position 359 to 362, causing a translational frameshift with a predicted alternate stop codon after 44 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 22% 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, this alteration has an overall frequency of 0.01% (20/251474) total alleles studied. The highest observed frequency was 0.01% (5/34592) of Latino alleles. Based on the available evidence, this alteration is classified as likely pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 12, 2022This sequence change creates a premature translational stop signal (p.Ile120Lysfs*44) in the NDUFA6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the NDUFA6 protein. This variant is present in population databases (rs768463498, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NDUFA6-related conditions. This variant is also known as c22_42482290: del_TTAA. ClinVar contains an entry for this variant (Variation ID: 1324784). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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.

Other links and lift over

dbSNP: rs768463498; hg19: chr22-42482289; API