8-95045599-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3PP5

The NM_152416.4(NDUFAF6):c.532G>C(p.Ala178Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000992 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NDUFAF6
NM_152416.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 4.28

Publications

7 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant 8-95045599-G-C is Pathogenic according to our data. Variant chr8-95045599-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372254.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF6	NM_152416.4 link	c.532G>C	p.Ala178Pro	missense_variant	Exon 5 of 9	ENST00000396124.9	NP_689629.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF6	ENST00000396124.9 link	c.532G>C	p.Ala178Pro	missense_variant	Exon 5 of 9	2	NM_152416.4	ENSP00000379430.4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000112

AC:

AN:

249340

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461240

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1111678

Other (OTH)

AF:

0.000116

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

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:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000118

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000275

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.000166

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 17

Pathogenic:5

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.A178P in NDUFAF6 (NM_152416.4) has been reported in an affected patient in compound heterozygous state with a deep intronic variant (Bianciardi L et al).Functional studies revealed a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.A178P missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.532 in NDUFAF6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic

Jun 23, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 17, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.72 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372254 /PMID: 27623250). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29531337). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: C8orf38 c.532G>C (p.Ala178Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 280728 control chromosomes. c.532G>C has been reported in the literature in trans along with a pathogenic intronic variant in multiple individuals affected with Leigh syndrome (example, Bianciardi_2016, Catania_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced normal complex I activity in patients fibroblasts, which was rescued by normal C8ORF38 (Bianciardi_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27623250, 29531337). ClinVar contains an entry for this variant (Variation ID: 372254). Based on the evidence outlined above, the variant was classified as pathogenic.

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Mitochondrial complex I deficiency, nuclear type 17 (MIM#618239). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SQS_PSY domain (PDB, DECIPHER, NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. Three unrelated probands with Leigh syndrome have been reported to be compound heterozygotes with this variant (PMID: 29531337). (SP) 0903 - This variant has insufficient evidence for segregation with disease. A single family with two affected siblings has been reported (PMID: 29531337). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

not provided

Pathogenic:2Uncertain:1

Oct 16, 2024

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the NDUFAF6 protein (p.Ala178Pro). This variant is present in population databases (rs201088736, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of complex 1 deficiency and/or complex 1 deficiency (PMID: 29531337). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372254). 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 expected to disrupt NDUFAF6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Nov 04, 2024

GeneDx

Significance:Uncertain significance

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: 34426522, 31589614, 27623250, 33097395, 29531337)

Inborn genetic diseases

Uncertain:1

Nov 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.532G>C (p.A178P) alteration is located in exon 5 (coding exon 5) of the NDUFAF6 gene. This alteration results from a G to C substitution at nucleotide position 532, causing the alanine (A) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

See cases

Uncertain:1

Mar 12, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2, PP3, PP5

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T;D;T;D;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;.;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D

MetaSVM

Uncertain

-0.086

MutationAssessor

Benign

0.0

.;.;.;.;M;.

PhyloP100

4.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

D;D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0070

D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Vest4

0.0

ClinPred

0.86

GERP RS

4.9

Varity_R

0.97

gMVP

0.95

Mutation Taster

=5/95

disease causing (ClinVar)

(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