12-94971904-A-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018838.5(NDUFA12):c.258-285_258-284insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 557,988 control chromosomes in the GnomAD database, including 222 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 32)
  • Exomes 𝑓: 0.019 (126 hom.)
• Consequence: NDUFA12 NM_018838.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.314

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 12-94971904-A-AT is Benign according to our data. Variant chr12-94971904-A-AT is described in ClinVar as [Benign]. Clinvar id is 1291707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3125/151358) while in subpopulation NFE AF= 0.0223 (1509/67812). AF 95% confidence interval is 0.0213. There are 96 homozygotes in gnomad4. There are 1788 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 96 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA12	NM_018838.5	c.258-285_258-284insA		intron_variant		ENST00000327772.7
NDUFA12	NM_001258338.2	c.170-285_170-284insA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA12	ENST00000327772.7	c.258-285_258-284insA		intron_variant		1	NM_018838.5	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3126 AN: 151244 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0190 AC: 7737 AN: 406630 Hom.: 126 AF XY: 0.0179 AC XY: 3919 AN XY: 218710

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.00866

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.00182

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0205

GnomAD4 genome AF: 0.0206 AC: 3125 AN: 151358 Hom.: 96 Cov.: 32 AF XY: 0.0242 AC XY: 1788 AN XY: 73920

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0223

Gnomad4 OTH AF: 0.0138

Bravo AF: 0.0122

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138810463; hg19: chr12-95365680;