NM_152416.4:c.532G>A

Variant names:

• chr8-95045599-G-A
• rs201088736
• NM_152416.4:c.532G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_152416.4(NDUFAF6):​c.532G>A​(p.Ala178Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A178P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.28
• Publications: 0 publications found

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 disease

  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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-95045599-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372254.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	NM_152416.4	MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 5 of 9	NP_689629.2	Q330K2-1
	NDUFAF6	NM_001354516.2		c.376G>A	p.Ala126Thr	missense	Exon 7 of 11	NP_001341445.1	Q330K2-2
	NDUFAF6	NM_001330582.2		c.256G>A	p.Ala86Thr	missense	Exon 5 of 9	NP_001317511.1	A0A075B6P0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 5 of 9	ENSP00000379430.4	Q330K2-1
	NDUFAF6	ENST00000875013.1		c.532G>A	p.Ala178Thr	missense	Exon 5 of 9	ENSP00000545072.1
	NDUFAF6	ENST00000940120.1		c.532G>A	p.Ala178Thr	missense	Exon 5 of 8	ENSP00000610179.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461244 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.024	D
Polyphen		0.80	P
Vest4		0.66
MutPred		0.64		Gain of loop (P = 0.1069)
MVP		0.80
MPC		0.60
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.31
gMVP		0.75
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs201088736; hg19: chr8-96057827;