8-95035527-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_152416.4(NDUFAF6):c.371T>C(p.Ile124Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 2 hom. )

Consequence

NDUFAF6
NM_152416.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 7.47

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency, nuclear type 17
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
primary Fanconi syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi renotubular syndrome 5
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NDUFAF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 8-95035527-T-C is Pathogenic according to our data. Variant chr8-95035527-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214212.

BP4

Computational evidence support a benign effect (MetaRNN=0.17004153). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF6	NM_152416.4 link	c.371T>C	p.Ile124Thr	missense_variant	Exon 3 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.371T>C	p.Ile124Thr	missense_variant	Exon 3 of 9	2	NM_152416.4	ENSP00000379430.4		Q330K2-1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

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:

0.0000922

AC:

AN:

249420

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000779

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.000757

AC:

AN:

39628

South Asian (SAS)

AF:

0.000186

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111754

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000330

AC:

AN:

151618

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74008

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41314

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000315

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 17

Pathogenic:3

Apr 15, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.I124T in NDUFAF6 (NM_152416.4) has been reported previously in patients affected with mitochondrial disease in compound heterozygous state (Kohda M, et al). It has been submitted to ClinVar as Variant of uncertain significance. The variant has been detected in homozygous state in two affected siblings with Leigh disease within one of the submitting labs in ClinVar. The p.I124T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.371 in NDUFAF6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM3_VeryStrong+PP4+PP1_Moderate -

not provided

Pathogenic:2

Feb 07, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26741492, 28429146, 30642748, 31967322, 32348839, 34988976, 35094435, 35664867) -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the NDUFAF6 protein (p.Ile124Thr). This variant is present in population databases (rs201732170, gnomAD 0.08%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 26741492, 30642748, 31967322, 32348839). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214212). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NDUFAF6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Leigh syndrome

Uncertain:2

Aug 14, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Ile124Thr variant in NDUFAF6 was identified by our study in two siblings with Leigh syndrome. The p.Ile124Thr variant in NDUFAF6 has been reported in 2 Japanese individuals with Leigh syndrome (PMID: 26741492) and has been identified in 0.07952% (15/18862) of East Asian chromosomes and 0.01949% (6/30780) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201732170). This variant has also been reported as a VUS in ClinVar (Variation ID: 214212). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with 2 variants reported pathogenic in the literature and OMIM and in 2 individuals with Leigh syndrome increases the likelihood that the p.Ile124Thr variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

.;T;T;T;D;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.;D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Uncertain

0.044

MutationAssessor

Benign

1.3

.;.;.;.;L;.

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.2

N;D;N;D;D;N

REVEL

Uncertain

0.54

Sift

Benign

0.69

T;T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T;T

Polyphen

0.26

.;.;.;.;B;.

Vest4

0.83, 0.83, 0.85

MVP

0.85

MPC

0.33

ClinPred

0.14

GERP RS

5.5

Varity_R

0.30

gMVP

0.62

Mutation Taster

=1/99

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over