dbSNP rs142609245: NDUFB3:p.Trp22Arg (chr2-201078946-T-C) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PM2PP2PP3PP5_Very_Strong

The NM_002491.3(NDUFB3):c.64T>C(p.Trp22Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00166 in 1,613,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000513887: Expression of W22R into patient fibroblasts failed to rescue mitochondrial complex I deficiency, while expression of wild-type NDUFB3 rescued complex I activity (Haack et al., 2012)" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 0 hom. )

Consequence

NDUFB3
NM_002491.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.71

Publications

18 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: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000513887: Expression of W22R into patient fibroblasts failed to rescue mitochondrial complex I deficiency, while expression of wild-type NDUFB3 rescued complex I activity (Haack et al., 2012);; SCV002817324: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22277967, 22499348, 27091925).; SCV003274971: Experimental studies have shown that this missense change affects NDUFB3 function (PMID: 27091925).; SCV000740859: Complementation studies demonstrated that the p.W22R alteration produced decreased complex I activity (Calvo, 2012; Haack, 2012).; SCV002548243: At least one publication reports experimental evidence evaluating an impact on protein function and showed that protein with this variant could not rescue NDUFB3 deficiency.; SCV006585975: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 22277967, 22499348).

PM2

Variant has high frequency in the NFE (0.00198) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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, nuclear type 25, mitochondrial disease, mitochondrial complex I deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

PP5

Variant 2-201078946-T-C is Pathogenic according to our data. Variant chr2-201078946-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.64T>C	p.Trp22Arg	missense	Exon 2 of 3	NP_002482.1	O43676
	NDUFB3	NM_001257102.2		c.64T>C	p.Trp22Arg	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.64T>C	p.Trp22Arg	missense	Exon 2 of 3	ENSP00000237889.4	O43676
NDUFB3	ENST00000433898.5	TSL:2	c.64T>C	p.Trp22Arg	missense	Exon 3 of 4	ENSP00000410600.1	O43676
NDUFB3	ENST00000450023.6	TSL:3	c.64T>C	p.Trp22Arg	missense	Exon 2 of 3	ENSP00000401834.2	O43676

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000853

AC:

214

AN:

250986

AF XY:

0.000929

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00172

AC:

2515

AN:

1461100

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1240

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33458

American (AMR)

AF:

0.000716

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000452

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5520

European-Non Finnish (NFE)

AF:

0.00205

AC:

2281

AN:

1111682

Other (OTH)

AF:

0.00237

AC:

143

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

121

242

362

483

604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

196

294

392

490

<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:

0.00112

AC:

171

AN:

152174

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41520

American (AMR)

AF:

0.00308

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

67998

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00251

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial complex I deficiency, nuclear type 25 (8)

not provided (6)

Inborn genetic diseases (1)

Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.49

PhyloP100

6.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-9.3

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.73

Gain of disorder (P = 9e-04)

MVP

0.97

MPC

0.38

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.88

Mutation Taster

=2/98

disease causing (ClinVar)

(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