8-124549788-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005005.3(NDUFB9):c.436C>T(p.Pro146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,613,860 control chromosomes in the GnomAD database, including 7,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 826 hom., cov: 32)

Exomes 𝑓: 0.093 ( 6790 hom. )

Consequence

NDUFB9
NM_005005.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.509

Publications

36 publications found

Variant links:

Genes affected

NDUFB9 (HGNC:7704): (NADH:ubiquinone oxidoreductase subunit B9) The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

NDUFB9 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency, nuclear type 24
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

NDUFB9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011136234).

BP6

Variant 8-124549788-C-T is Benign according to our data. Variant chr8-124549788-C-T is described in ClinVar as Benign. ClinVar VariationId is 138469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFB9	NM_005005.3	MANE Select	c.436C>T	p.Pro146Ser	missense	Exon 4 of 4	NP_004996.1
NDUFB9	NM_001311168.2		c.403C>T	p.Pro135Ser	missense	Exon 4 of 4	NP_001298097.1
NDUFB9	NM_001278646.2		c.307C>T	p.Pro103Ser	missense	Exon 4 of 4	NP_001265575.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFB9	ENST00000276689.8	TSL:1 MANE Select	c.436C>T	p.Pro146Ser	missense	Exon 4 of 4	ENSP00000276689.3
NDUFB9	ENST00000901305.1		c.535C>T	p.Pro179Ser	missense	Exon 5 of 5	ENSP00000571364.1
NDUFB9	ENST00000928469.1		c.433C>T	p.Pro145Ser	missense	Exon 4 of 4	ENSP00000598528.1

Frequencies

GnomAD3 genomes

AF:

0.0968

AC:

14710

AN:

152026

Hom.:

825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0618

Gnomad ASJ

AF:

0.0510

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.0742

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0893

Gnomad OTH

AF:

0.0866

GnomAD2 exomes

AF:

0.0920

AC:

23108

AN:

251200

AF XY:

0.0917

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.0538

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.0884

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.0925

AC:

135268

AN:

1461714

Hom.:

6790

Cov.:

AF XY:

0.0917

AC XY:

66678

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.111

AC:

3723

AN:

33478

American (AMR)

AF:

0.0428

AC:

1915

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0537

AC:

1404

AN:

26136

East Asian (EAS)

AF:

0.198

AC:

7854

AN:

39694

South Asian (SAS)

AF:

0.0722

AC:

6230

AN:

86258

European-Finnish (FIN)

AF:

0.158

AC:

8437

AN:

53408

Middle Eastern (MID)

AF:

0.112

AC:

644

AN:

5760

European-Non Finnish (NFE)

AF:

0.0893

AC:

99314

AN:

1111872

Other (OTH)

AF:

0.0952

AC:

5747

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

6521

13041

19562

26082

32603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3756

7512

11268

15024

18780

<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:

0.0967

AC:

14710

AN:

152146

Hom.:

826

Cov.:

AF XY:

0.0986

AC XY:

7334

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.104

AC:

4310

AN:

41518

American (AMR)

AF:

0.0618

AC:

946

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

177

AN:

3470

East Asian (EAS)

AF:

0.169

AC:

876

AN:

5172

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4822

European-Finnish (FIN)

AF:

0.159

AC:

1684

AN:

10566

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0893

AC:

6070

AN:

67978

Other (OTH)

AF:

0.0861

AC:

182

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

655

1310

1965

2620

3275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.0904

Hom.:

2588

Bravo

AF:

0.0913

TwinsUK

AF:

0.0866

AC:

321

ALSPAC

AF:

0.0820

AC:

316

ESP6500AA

AF:

0.103

AC:

452

ESP6500EA

AF:

0.0842

AC:

724

ExAC

AF:

0.0926

AC:

11240

Asia WGS

AF:

0.107

AC:

371

AN:

3478

EpiCase

AF:

0.0841

EpiControl

AF:

0.0833

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.2

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.037

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

-0.51

PrimateAI

Benign

0.21

PROVEAN

Benign

0.0

REVEL

Benign

0.13

Sift

Benign

0.53

Sift4G

Benign

0.21

Polyphen

0.0070

Vest4

0.066

MPC

0.23

ClinPred

0.0081

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.26

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over