rs249167

Variant names:

• chr12-94936497-T-A
• rs249167
• ENST00000552205.6:n.258-8234A>T

Variant summary

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

The ENST00000552205.6(NDUFA12):​n.258-8234A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 152,128 control chromosomes in the GnomAD database, including 4,793 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 0.24 (4793 hom., cov: 33)
• Consequence: NDUFA12 ENST00000552205.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371
• Publications: 4 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000552205.6. 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	ENST00000552205.6	TSL:5	n.258-8234A>T		intron	N/A	ENSP00000449144.2	H0YID5

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36325 AN: 152010 Hom.: 4788 Cov.: 33

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.239 AC: 36342 AN: 152128 Hom.: 4793 Cov.: 33 AF XY: 0.235 AC XY: 17466 AN XY: 74346

African (AFR) AF: 0.352 AC: 14622 AN: 41484

American (AMR) AF: 0.186 AC: 2842 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 643 AN: 3468

East Asian (EAS) AF: 0.179 AC: 920 AN: 5154

South Asian (SAS) AF: 0.137 AC: 662 AN: 4828

European-Finnish (FIN) AF: 0.158 AC: 1680 AN: 10600

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

European-Non Finnish (NFE) AF: 0.209 AC: 14225 AN: 67990

Other (OTH) AF: 0.230 AC: 483 AN: 2104

Alfa AF: 0.236 Hom.: 579

Bravo AF: 0.245

Asia WGS AF: 0.185 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.82
PhyloP100		-0.37

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: rs249167;

hg19: chr12-95330273;