rs762093523

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152416.4(NDUFAF6):c.485delA(p.Asn162IlefsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NDUFAF6
NM_152416.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.14

Variant links:

Genes affected

NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

NDUFAF6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-95045545-GA-G is Pathogenic according to our data. Variant chr8-95045545-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF6	NM_152416.4 link	c.485delA	p.Asn162IlefsTer27	frameshift_variant	Exon 5 of 9	ENST00000396124.9	NP_689629.2	Q330K2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF6	ENST00000396124.9 link	c.485delA	p.Asn162IlefsTer27	frameshift_variant	Exon 5 of 9	2	NM_152416.4	ENSP00000379430.4		Q330K2-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152006

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248968

AF XY:

0.00000740

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1458384

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33394

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44706

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26090

Gnomad4 EAS exome

AF:

0.0000253

AC:

AN:

39510

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86138

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53326

Gnomad4 NFE exome

AF:

0.00000270

AC:

AN:

1109210

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147054

AN:

0.0000147054

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Asia WGS

AF:

0.000289

AC:

AN:

3468

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 09, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in trans with an intronic variant in an individual with suspected mitochondrial disease with symptoms including regression, dystonia and abnormal MRI (PMID: 37377599); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37377599) -

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asn162Ilefs*27) in the NDUFAF6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF6 are known to be pathogenic (PMID: 28639102, 30642748). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 37377599). This variant is also known as c.479delA. ClinVar contains an entry for this variant (Variation ID: 1064697). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex 1 deficiency, nuclear type 17

Pathogenic:1

Dec 25, 2020

Istanbul Faculty of Medicine, Istanbul University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Affected patient is compound heterozygous with c.420+784C>T in trans allele -

Mitochondrial complex 1 deficiency, nuclear type 17;C5394473:Fanconi renotubular syndrome 5

Pathogenic:1

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=5/195

disease causing (fs/PTC)

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

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