12-94928357-C-T

Variant names:

• chr12-94928357-C-T
• rs2033092
• ENST00000552205.6:n.258-94G>A

Variant summary

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

The ENST00000552205.6(NDUFA12):​n.258-94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 453,596 control chromosomes in the GnomAD database, including 35,473 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 0.39 (11743 hom., cov: 32)
  • Exomes 𝑓: 0.40 (23730 hom.)
• Consequence: NDUFA12 ENST00000552205.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105369915	XR_001749264.2	n.-99G>A		upstream_gene_variant
LOC105369915	XR_945226.2	n.-99G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA12	ENST00000552205.6	n.258-94G>A		intron_variant	Intron 3 of 5	5		ENSP00000449144.2

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59526 AN: 151822 Hom.: 11735 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.395 AC: 119267 AN: 301656 Hom.: 23730 AF XY: 0.396 AC XY: 68097 AN XY: 171826

African (AFR) AF: 0.406 AC: 3477 AN: 8564

American (AMR) AF: 0.424 AC: 11497 AN: 27126

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 4019 AN: 10690

East Asian (EAS) AF: 0.392 AC: 3605 AN: 9204

South Asian (SAS) AF: 0.410 AC: 24346 AN: 59394

European-Finnish (FIN) AF: 0.418 AC: 5153 AN: 12336

Middle Eastern (MID) AF: 0.399 AC: 848 AN: 2124

European-Non Finnish (NFE) AF: 0.385 AC: 60934 AN: 158114

Other (OTH) AF: 0.382 AC: 5388 AN: 14104

GnomAD4 genome AF: 0.392 AC: 59558 AN: 151940 Hom.: 11743 Cov.: 32 AF XY: 0.395 AC XY: 29295 AN XY: 74232

African (AFR) AF: 0.398 AC: 16500 AN: 41430

American (AMR) AF: 0.402 AC: 6143 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1343 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1969 AN: 5172

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4814

European-Finnish (FIN) AF: 0.428 AC: 4495 AN: 10512

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25910 AN: 67956

Other (OTH) AF: 0.389 AC: 821 AN: 2108

Alfa AF: 0.385 Hom.: 21165

Bravo AF: 0.388

Asia WGS AF: 0.406 AC: 1412 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	2.5
DANN	Benign	0.82
PhyloP100		-0.18

Splicing

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

Other links and lift over

dbSNP: rs2033092; hg19: chr12-95322133; COSMIC: COSV73524815;