rs249154

Variant names:

• chr12-94930780-G-C
• rs249154
• ENST00000552205.6:n.258-2517C>G

Variant summary

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

The ENST00000552205.6(NDUFA12):​n.258-2517C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,164 control chromosomes in the GnomAD database, including 4,242 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 (4242 hom., cov: 32)
• Consequence: NDUFA12 ENST00000552205.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 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.258-2517C>G		intron_variant	Intron 3 of 5	5		ENSP00000449144.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34303 AN: 152046 Hom.: 4235 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0882

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.226 AC: 34321 AN: 152164 Hom.: 4242 Cov.: 32 AF XY: 0.222 AC XY: 16492 AN XY: 74378

African (AFR) AF: 0.318 AC: 13206 AN: 41480

American (AMR) AF: 0.181 AC: 2761 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3472

East Asian (EAS) AF: 0.0881 AC: 457 AN: 5190

South Asian (SAS) AF: 0.126 AC: 610 AN: 4824

European-Finnish (FIN) AF: 0.154 AC: 1634 AN: 10590

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

European-Non Finnish (NFE) AF: 0.210 AC: 14279 AN: 67996

Other (OTH) AF: 0.220 AC: 466 AN: 2116

Alfa AF: 0.231 Hom.: 545

Bravo AF: 0.230

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	-0.89
CADD	Benign	4.2
DANN	Benign	0.57
PhyloP100		0.12

Splicing

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

Other links and lift over

dbSNP: rs249154; hg19: chr12-95324556;