9-122152334-C-T

Variant names:

• chr9-122152334-C-T
• rs4679
• NM_014222.3:c.126G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014222.3(NDUFA8):​c.126G>A​(p.Glu42Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.562 in 1,613,720 control chromosomes in the GnomAD database, including 266,611 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 0.44 (17912 hom., cov: 31)
  • Exomes 𝑓: 0.57 (248699 hom.)
• Consequence: NDUFA8 NM_014222.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62
• Publications: 41 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA8	NM_014222.3	c.126G>A	p.Glu42Glu	synonymous_variant	Exon 2 of 4	ENST00000373768.4	NP_055037.1
NDUFA8	NM_001318195.2	c.126G>A	p.Glu42Glu	synonymous_variant	Exon 2 of 4		NP_001305124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA8	ENST00000373768.4	c.126G>A	p.Glu42Glu	synonymous_variant	Exon 2 of 4	1	NM_014222.3	ENSP00000362873.3

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67018 AN: 151816 Hom.: 17921 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.506 AC: 127077 AN: 251254 AF XY: 0.519

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.549

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.575 AC: 839816 AN: 1461786 Hom.: 248699 Cov.: 53 AF XY: 0.575 AC XY: 418044 AN XY: 727184

African (AFR) AF: 0.138 AC: 4633 AN: 33480

American (AMR) AF: 0.429 AC: 19180 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 14608 AN: 26132

East Asian (EAS) AF: 0.242 AC: 9603 AN: 39700

South Asian (SAS) AF: 0.526 AC: 45369 AN: 86256

European-Finnish (FIN) AF: 0.553 AC: 29554 AN: 53412

Middle Eastern (MID) AF: 0.519 AC: 2996 AN: 5768

European-Non Finnish (NFE) AF: 0.613 AC: 681787 AN: 1111930

Other (OTH) AF: 0.531 AC: 32086 AN: 60394

GnomAD4 genome AF: 0.441 AC: 67008 AN: 151934 Hom.: 17912 Cov.: 31 AF XY: 0.438 AC XY: 32528 AN XY: 74198

African (AFR) AF: 0.152 AC: 6295 AN: 41462

American (AMR) AF: 0.446 AC: 6809 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1956 AN: 3472

East Asian (EAS) AF: 0.225 AC: 1166 AN: 5172

South Asian (SAS) AF: 0.510 AC: 2450 AN: 4800

European-Finnish (FIN) AF: 0.542 AC: 5704 AN: 10516

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.602 AC: 40931 AN: 67942

Other (OTH) AF: 0.478 AC: 1011 AN: 2114

Alfa AF: 0.546 Hom.: 27414

Bravo AF: 0.419

Asia WGS AF: 0.342 AC: 1191 AN: 3478

EpiCase AF: 0.613

EpiControl AF: 0.615

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.63
PhyloP100		3.6
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4679; hg19: chr9-124914613; COSMIC: COSV65653264;