chr2-201078901-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_002491.3(NDUFB3):c.19C>T(p.His7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,610,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H7P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

NDUFB3
NM_002491.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.04

Publications

8 publications found

Variant links:

Genes affected

NDUFB3 (HGNC:7698): (NADH:ubiquinone oxidoreductase subunit B3) This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

NDUFB3 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 25
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.31597 (below the threshold of 3.09). Trascript score misZ: 0.8038 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, mitochondrial complex I deficiency, nuclear type 25, mitochondrial disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.051812947).

BP6

Variant 2-201078901-C-T is Benign according to our data. Variant chr2-201078901-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214762.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002491.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	NM_002491.3	MANE Select	c.19C>T	p.His7Tyr	missense	Exon 2 of 3	NP_002482.1	O43676
	NDUFB3	NM_001257102.2		c.19C>T	p.His7Tyr	missense	Exon 3 of 4	NP_001244031.1	O43676

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFB3	ENST00000237889.9	TSL:1 MANE Select	c.19C>T	p.His7Tyr	missense	Exon 2 of 3	ENSP00000237889.4	O43676
NDUFB3	ENST00000433898.5	TSL:2	c.19C>T	p.His7Tyr	missense	Exon 3 of 4	ENSP00000410600.1	O43676
NDUFB3	ENST00000450023.6	TSL:3	c.19C>T	p.His7Tyr	missense	Exon 2 of 3	ENSP00000401834.2	O43676

Frequencies

GnomAD3 genomes

AF:

0.000658

AC:

100

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000885

AC:

221

AN:

249836

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000591

AC:

862

AN:

1458840

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

509

AN XY:

725748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.0000451

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00153

AC:

131

AN:

85754

European-Finnish (FIN)

AF:

0.00185

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00109

AC:

AN:

4602

European-Non Finnish (NFE)

AF:

0.000505

AC:

561

AN:

1111430

Other (OTH)

AF:

0.000947

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000657

AC:

100

AN:

152096

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41484

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00145

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000800

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00114

AC:

139

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.052

MetaSVM

Uncertain

-0.11

PhyloP100

3.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.018

Sift4G

Uncertain

0.022

Polyphen

0.94

Vest4

0.37

MVP

0.92

MPC

0.11

ClinPred

0.084

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.60

Mutation Taster

=98/2

polymorphism

(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