Genetic Variant NM_014222.3:c.382-66A>G (chr9-122144444-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014222.3(NDUFA8):c.382-66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,498,066 control chromosomes in the GnomAD database, including 422,053 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 0.76 ( 44464 hom., cov: 33)

Exomes 𝑓: 0.75 ( 377589 hom. )

Consequence

NDUFA8
NM_014222.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

Publications

14 publications found

Variant links:

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)

NDUFA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA8	NM_014222.3 link	c.382-66A>G		intron_variant	Intron 3 of 3	ENST00000373768.4	NP_055037.1	P51970
NDUFA8	NM_001318195.2 link	c.381+3668A>G		intron_variant	Intron 3 of 3		NP_001305124.1	B7Z768

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA8	ENST00000373768.4 link	c.382-66A>G		intron_variant	Intron 3 of 3	1	NM_014222.3	ENSP00000362873.3		P51970

Frequencies

GnomAD3 genomes

AF:

0.760

AC:

115571

AN:

152072

Hom.:

44440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.829

Gnomad AMI

AF:

0.703

Gnomad AMR

AF:

0.711

Gnomad ASJ

AF:

0.766

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.681

Gnomad FIN

AF:

0.770

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.740

GnomAD4 exome

AF:

0.746

AC:

1004298

AN:

1345876

Hom.:

377589

AF XY:

0.745

AC XY:

503286

AN XY:

675654

show subpopulations

African (AFR)

AF:

0.833

AC:

25855

AN:

31038

American (AMR)

AF:

0.684

AC:

30384

AN:

44422

Ashkenazi Jewish (ASJ)

AF:

0.767

AC:

19486

AN:

25404

East Asian (EAS)

AF:

0.419

AC:

16334

AN:

39020

South Asian (SAS)

AF:

0.700

AC:

58510

AN:

83538

European-Finnish (FIN)

AF:

0.768

AC:

40943

AN:

53306

Middle Eastern (MID)

AF:

0.712

AC:

3874

AN:

5444

European-Non Finnish (NFE)

AF:

0.762

AC:

767540

AN:

1007138

Other (OTH)

AF:

0.731

AC:

41372

AN:

56566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

13533

27066

40599

54132

67665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17704

35408

53112

70816

88520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.760

AC:

115643

AN:

152190

Hom.:

44464

Cov.:

AF XY:

0.755

AC XY:

56163

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.829

AC:

34425

AN:

41522

American (AMR)

AF:

0.711

AC:

10865

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

2657

AN:

3470

East Asian (EAS)

AF:

0.410

AC:

2117

AN:

5162

South Asian (SAS)

AF:

0.680

AC:

3277

AN:

4822

European-Finnish (FIN)

AF:

0.770

AC:

8154

AN:

10590

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.760

AC:

51730

AN:

68022

Other (OTH)

AF:

0.737

AC:

1560

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1376

2752

4127

5503

6879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.756

Hom.:

191285

Bravo

AF:

0.756

Asia WGS

AF:

0.581

AC:

2022

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.90

(source)

DANN

Benign

0.41

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over