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:6U: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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152416.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFAF6	NM_152416.4	MANE Select	c.371T>C	p.Ile124Thr	missense	Exon 3 of 9	NP_689629.2
NDUFAF6	NM_001354516.2		c.215T>C	p.Ile72Thr	missense	Exon 5 of 11	NP_001341445.1
NDUFAF6	NM_001330582.2		c.95T>C	p.Ile32Thr	missense	Exon 3 of 9	NP_001317511.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.371T>C	p.Ile124Thr	missense	Exon 3 of 9	ENSP00000379430.4
NDUFAF6	ENST00000875013.1		c.371T>C	p.Ile124Thr	missense	Exon 3 of 9	ENSP00000545072.1
NDUFAF6	ENST00000940120.1		c.371T>C	p.Ile124Thr	missense	Exon 3 of 8	ENSP00000610179.1

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

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial complex I deficiency, nuclear type 17 (4)

Leigh syndrome (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.028

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.044

MutationAssessor

Benign

1.3

PhyloP100

7.5

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.54

Sift

Benign

0.69

Sift4G

Benign

0.54

Polyphen

0.26

Vest4

0.83

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over