8-95045599-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 4.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 372254.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=3, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF6	NM_152416.4	c.532G>C	p.Ala178Pro	missense_variant	5/9	ENST00000396124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF6	ENST00000396124.9	c.532G>C	p.Ala178Pro	missense_variant	5/9	2	NM_152416.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152170 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 249340 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135280

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 SAS 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.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000166 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 17 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2024	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. This frequency is not significantly higher than estimated for a pathogenic variant in C8orf38 causing Mitochondrial Complex 1 Deficiency, Nuclear Type 17 (0.0001 vs ND), allowing no conclusion about variant significance. c.532G>C has been reported in the literature in individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 17. These data indicate that the variant is 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 <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 372254). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 23, 2020	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2021	This variant is associated with the following publications: (PMID: 29531337, 27623250) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDUFAF6 protein function. ClinVar contains an entry for this variant (Variation ID: 372254). 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. This variant is present in population databases (rs201088736, gnomAD 0.02%). 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). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 12, 2019

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	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	-0.086	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
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
Polyphen		0.99	.;.;.;.;D;.
Vest4		0.88, 0.87, 0.86
MVP		0.83
MPC		0.79
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.95

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

Other links and lift over

dbSNP: rs201088736; hg19: chr8-96057827;