NM_152416.4:c.83G>C

Variant names:

• chr8-95025091-G-C
• rs201223057
• NM_152416.4:c.83G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152416.4(NDUFAF6):​c.83G>C​(p.Gly28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,481,506 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G28R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.09
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051229).
• BP6: Variant 8-95025091-G-C is Benign according to our data. Variant chr8-95025091-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 214210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00339 (4504/1329208) while in subpopulation NFE AF = 0.00377 (3994/1058736). AF 95% confidence interval is 0.00367. There are 11 homozygotes in GnomAdExome4. There are 2191 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	NM_152416.4	MANE Select	c.83G>C	p.Gly28Ala	missense	Exon 1 of 9	NP_689629.2	Q330K2-1
	NDUFAF6	NM_001330582.2		c.-198G>C		5_prime_UTR	Exon 1 of 9	NP_001317511.1	A0A075B6P0
	NDUFAF6	NM_001354517.2		c.-151G>C		5_prime_UTR	Exon 1 of 8	NP_001341446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.83G>C	p.Gly28Ala	missense	Exon 1 of 9	ENSP00000379430.4	Q330K2-1
	NDUFAF6	ENST00000875013.1		c.83G>C	p.Gly28Ala	missense	Exon 1 of 9	ENSP00000545072.1
	NDUFAF6	ENST00000940120.1		c.83G>C	p.Gly28Ala	missense	Exon 1 of 8	ENSP00000610179.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00135 AC: 117 AN: 86834 AF XY: 0.00139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00339 AC: 4504 AN: 1329208 Hom.: 11 Cov.: 31 AF XY: 0.00334 AC XY: 2191 AN XY: 656182

African (AFR) AF: 0.000442 AC: 12 AN: 27132

American (AMR) AF: 0.000494 AC: 13 AN: 26318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22716

East Asian (EAS) AF: 0.00 AC: 0 AN: 29586

South Asian (SAS) AF: 0.00203 AC: 147 AN: 72268

European-Finnish (FIN) AF: 0.00538 AC: 178 AN: 33072

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4118

European-Non Finnish (NFE) AF: 0.00377 AC: 3994 AN: 1058736

Other (OTH) AF: 0.00280 AC: 155 AN: 55262

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74464

African (AFR) AF: 0.000505 AC: 21 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10614

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00174

ExAC AF: 0.000773 AC: 79

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 17;C5394473:Fanconi renotubular syndrome 5 (1)
-	-	1	NDUFAF6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.18
Sift	Benign	0.17	T
Sift4G	Benign	0.80	T
Polyphen		0.088	B
Vest4		0.22
MVP		0.088
MPC		0.18
ClinPred		0.024	T
GERP RS		-0.40
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.033
gMVP		0.22
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201223057; hg19: chr8-96037319;