9-122143760-T-C

Variant names:

• chr9-122143760-T-C
• rs4147659
• NM_001318195.2:c.381+4352A>G

Variant summary

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

The NM_001318195.2(NDUFA8):​c.381+4352A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,200 control chromosomes in the GnomAD database, including 11,247 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 0.32 (11247 hom., cov: 33)
• Consequence: NDUFA8 NM_001318195.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827
• Publications: 1 publications found

Genes affected

NDUFA8 (HGNC:7692): (NADH:ubiquinone oxidoreductase subunit A8) The protein encoded by this gene belongs to the complex I 19 kDa subunit family. Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays an important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

NDUFA8 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 37

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA8	NM_001318195.2	c.381+4352A>G		intron_variant	Intron 3 of 3		NP_001305124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48018 AN: 152082 Hom.: 11223 Cov.: 33

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.316 AC: 48084 AN: 152200 Hom.: 11247 Cov.: 33 AF XY: 0.313 AC XY: 23317 AN XY: 74396

African (AFR) AF: 0.661 AC: 27425 AN: 41518

American (AMR) AF: 0.263 AC: 4024 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 702 AN: 3470

East Asian (EAS) AF: 0.185 AC: 956 AN: 5176

South Asian (SAS) AF: 0.169 AC: 818 AN: 4826

European-Finnish (FIN) AF: 0.233 AC: 2474 AN: 10596

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10984 AN: 68000

Other (OTH) AF: 0.253 AC: 535 AN: 2112

Alfa AF: 0.218 Hom.: 3867

Bravo AF: 0.333

Asia WGS AF: 0.229 AC: 796 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.70
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4147659; hg19: chr9-124906039;