12-94914317-A-G

Variant names:

• chr12-94914317-A-G
• rs7306940
• ENST00000547447.1:n.162-3974T>C

Variant summary

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

The ENST00000547447.1(NDUFA12):​n.162-3974T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 151,860 control chromosomes in the GnomAD database, including 26,286 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 0.58 (26286 hom., cov: 31)
• Consequence: NDUFA12 ENST00000547447.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 3 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105369915	XR_001749264.2	n.403+10329T>C		intron_variant	Intron 2 of 2
LOC105369915	XR_945226.2	n.404-3974T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA12	ENST00000547447.1	n.162-3974T>C		intron_variant	Intron 1 of 2	3
NDUFA12	ENST00000552205.6	n.*179+10329T>C		intron_variant	Intron 5 of 5	5		ENSP00000449144.2

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88511 AN: 151742 Hom.: 26268 Cov.: 31

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.583 AC: 88571 AN: 151860 Hom.: 26286 Cov.: 31 AF XY: 0.581 AC XY: 43108 AN XY: 74214

African (AFR) AF: 0.531 AC: 21989 AN: 41390

American (AMR) AF: 0.595 AC: 9076 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2154 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1577 AN: 5150

South Asian (SAS) AF: 0.525 AC: 2529 AN: 4816

European-Finnish (FIN) AF: 0.558 AC: 5885 AN: 10538

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43401 AN: 67926

Other (OTH) AF: 0.592 AC: 1247 AN: 2108

Alfa AF: 0.618 Hom.: 16195

Bravo AF: 0.581

Asia WGS AF: 0.484 AC: 1687 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.26
DANN	Benign	0.49
PhyloP100		-1.1

Splicing

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

Other links and lift over

dbSNP: rs7306940; hg19: chr12-95308093;