chr12-94994249-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_018838.5(NDUFA12):c.178C>T(p.Arg60*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

NDUFA12
NM_018838.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.99

Publications

8 publications found

Variant links:

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

NDUFA12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-94994249-G-A is Pathogenic according to our data. Variant chr12-94994249-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA12	NM_018838.5 link	c.178C>T	p.Arg60*	stop_gained	Exon 3 of 4	ENST00000327772.7	NP_061326.1	Q9UI09-1
NDUFA12	NM_001258338.2 link	c.169+8490C>T		intron_variant	Intron 2 of 2		NP_001245267.1	Q9UI09-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA12	ENST00000327772.7 link	c.178C>T	p.Arg60*	stop_gained	Exon 3 of 4	1	NM_018838.5	ENSP00000330737.2		Q9UI09-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251250

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111876

Other (OTH)

AF:

0.0000497

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000556

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 23

Pathogenic:3

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed stop gained c.178C>T (p.Arg60Ter) variant in NDUFA12 gene has been previously reported in homozygous state in multiple individuals affected with NDUFA12-related disorders (Ostergaard et al., 2011; Speer et al., 2020; Magrinelli et al., 2022). Experimental studies showed that this variant affects NDUFA12 function (Ostergaard et al., 2011). The p.Arg60Ter variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg60Ter in NDUFA12 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg60Ter) in the NDUFA12 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in NDUFA12 gene have been previously reported to be disease causing (Alfares et al., 2017). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 23 (MIM#618244). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Symptoms range from Leigh/Leigh-like syndrome to isolated optic atrophy (PMID: 35141356, 33715266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). Western blot analysis showed absence of NDUFA12 protein in fibroblasts of a homozygous patient and functional complementation by a baculovirus system showed restoration of complex I activity (PMID: 21617257). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (17 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (DECIPHER, PMID: 35141356). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar. This variant has also been observed in three unrelated homozygous individuals with Leigh/Leigh-like syndrome (PMID: 21617257, 35141356). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Mar 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22142868, 34426522, 34069703, 34849584, 34827632, 33715266, 35141356, 21617257, 32341820) -

Feb 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 31207). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 21617257, 32341820). This variant is present in population databases (rs387907139, gnomAD 0.04%). This sequence change creates a premature translational stop signal (p.Arg60*) in the NDUFA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFA12 are known to be pathogenic (PMID: 21617257, 28454995). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

PhyloP100

3.0

Vest4

0.48

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=12/188

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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chr12-94994249-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over