rs6538566

Variant names:

• chr12-94902782-A-C
• rs6538566
• ENST00000547447.1:n.273-5472T>G

Variant summary

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

The ENST00000547447.1(NDUFA12):​n.273-5472T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 150,250 control chromosomes in the GnomAD database, including 44,488 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 0.77 (44488 hom., cov: 27)
• Consequence: NDUFA12 ENST00000547447.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.572
• Publications: 7 publications found

Genes affected

NDUFA12 (HGNC:23987): (NADH:ubiquinone oxidoreductase subunit A12) This gene encodes a protein which is part of mitochondrial complex 1, part of the oxidative phosphorylation system in mitochondria. Complex 1 transfers electrons to ubiquinone from NADH which establishes a proton gradient for the generation of ATP. Mutations in this gene are associated with Leigh syndrome due to mitochondrial complex 1 deficiency. Pseudogenes of this gene are located on chromosomes 5 and 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

NDUFA12 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LOC105369915 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000547447.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA12	ENST00000547447.1	TSL:3	n.273-5472T>G		intron	N/A
	NDUFA12	ENST00000552205.6	TSL:5	n.*180-5472T>G		intron	N/A	ENSP00000449144.2	H0YID5

Frequencies

GnomAD3 genomes AF: 0.769 AC: 115428 AN: 150134 Hom.: 44454 Cov.: 27

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.783

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.775

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

GnomAD4 genome AF: 0.769 AC: 115512 AN: 150250 Hom.: 44488 Cov.: 27 AF XY: 0.769 AC XY: 56243 AN XY: 73098

African (AFR) AF: 0.762 AC: 31048 AN: 40752

American (AMR) AF: 0.788 AC: 11855 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2631 AN: 3460

East Asian (EAS) AF: 0.724 AC: 3691 AN: 5096

South Asian (SAS) AF: 0.735 AC: 3503 AN: 4768

European-Finnish (FIN) AF: 0.715 AC: 7105 AN: 9938

Middle Eastern (MID) AF: 0.777 AC: 227 AN: 292

European-Non Finnish (NFE) AF: 0.783 AC: 53164 AN: 67908

Other (OTH) AF: 0.776 AC: 1621 AN: 2088

Alfa AF: 0.778 Hom.: 196257

Bravo AF: 0.774

Asia WGS AF: 0.749 AC: 2604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.57

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6538566;

hg19: chr12-95296558;