12-94930613-T-C

Variant names:

• chr12-94930613-T-C
• rs249153
• ENST00000552205.6:n.258-2350A>G

Variant summary

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

The ENST00000552205.6(NDUFA12):​n.258-2350A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,116 control chromosomes in the GnomAD database, including 4,286 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 0.23 (4286 hom., cov: 32)
• Consequence: NDUFA12 ENST00000552205.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.48
• Publications: 12 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA12	ENST00000552205.6	n.258-2350A>G		intron_variant	Intron 3 of 5	5		ENSP00000449144.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34447 AN: 151994 Hom.: 4278 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.227 AC: 34467 AN: 152116 Hom.: 4286 Cov.: 32 AF XY: 0.223 AC XY: 16584 AN XY: 74380

African (AFR) AF: 0.321 AC: 13303 AN: 41490

American (AMR) AF: 0.180 AC: 2758 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3470

East Asian (EAS) AF: 0.0880 AC: 456 AN: 5184

South Asian (SAS) AF: 0.127 AC: 613 AN: 4824

European-Finnish (FIN) AF: 0.158 AC: 1673 AN: 10572

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14288 AN: 67976

Other (OTH) AF: 0.221 AC: 468 AN: 2114

Alfa AF: 0.211 Hom.: 15704

Bravo AF: 0.231

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.42
PhyloP100		-3.5

Splicing

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

Other links and lift over

dbSNP: rs249153; hg19: chr12-95324389;