rs4735339

Variant names:

• chr8-94962145-C-T
• rs4735339
• NM_001354516.2:c.-79+3966C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354516.2(NDUFAF6):​c.-79+3966C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 152,008 control chromosomes in the GnomAD database, including 19,927 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (19927 hom., cov: 33)
• Consequence: NDUFAF6 NM_001354516.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 9 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 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF6	NM_001354516.2	c.-79+3966C>T		intron_variant	Intron 2 of 10		NP_001341445.1
NDUFAF6	NM_001354514.2	c.-301+3966C>T		intron_variant	Intron 2 of 11		NP_001341443.1
NDUFAF6	NM_001354515.2	c.-84+3966C>T		intron_variant	Intron 2 of 9		NP_001341444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF6	ENST00000396111.6	c.-199+3966C>T		intron_variant	Intron 1 of 9	5		ENSP00000379417.1
NDUFAF6	ENST00000396113.5	c.-614+3966C>T		intron_variant	Intron 3 of 14	5		ENSP00000379419.1
NDUFAF6	ENST00000697364.1	c.-203+3966C>T		intron_variant	Intron 2 of 10			ENSP00000513278.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76962 AN: 151890 Hom.: 19916 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.530

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.507 AC: 77015 AN: 152008 Hom.: 19927 Cov.: 33 AF XY: 0.513 AC XY: 38131 AN XY: 74282

African (AFR) AF: 0.412 AC: 17073 AN: 41436

American (AMR) AF: 0.562 AC: 8586 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1759 AN: 3470

East Asian (EAS) AF: 0.722 AC: 3737 AN: 5174

South Asian (SAS) AF: 0.584 AC: 2816 AN: 4820

European-Finnish (FIN) AF: 0.561 AC: 5919 AN: 10550

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.520 AC: 35375 AN: 67970

Other (OTH) AF: 0.531 AC: 1120 AN: 2108

Alfa AF: 0.498 Hom.: 3165

Bravo AF: 0.504

Asia WGS AF: 0.595 AC: 2066 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.80
PhyloP100		-0.076
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4735339; hg19: chr8-95974373;