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), G2P, Ambry Genetics
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105369915	XR_001749264.2	n.404-5472T>G		intron_variant	Intron 2 of 2
LOC105369915	XR_945226.2	n.515-5472T>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA12	ENST00000547447.1	n.273-5472T>G		intron_variant	Intron 2 of 2	3
NDUFA12	ENST00000552205.6	n.*180-5472T>G		intron_variant	Intron 5 of 5	5		ENSP00000449144.2

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 v4.3

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

Other links and lift over

dbSNP: rs6538566; hg19: chr12-95296558;