rs142609245

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_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 (★★).

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: Ambry Genetics, G2P, 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 12 ACMG points.

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NDUFB3	NM_002491.3 link	c.64T>C	p.Trp22Arg	missense_variant	Exon 2 of 3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2 link	c.64T>C	p.Trp22Arg	missense_variant	Exon 3 of 4		NP_001244031.1
NDUFB3	XM_011511230.4 link	c.64T>C	p.Trp22Arg	missense_variant	Exon 3 of 4		XP_011509532.1
NDUFB3	XM_047444488.1 link	c.64T>C	p.Trp22Arg	missense_variant	Exon 3 of 4		XP_047300444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB3	ENST00000237889.9 link	c.64T>C	p.Trp22Arg	missense_variant	Exon 2 of 3	1	NM_002491.3	ENSP00000237889.4

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 25

Pathogenic:8

Dec 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 19, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.166%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 22277967, 22499348). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.09 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252575 /PMID: 22277967 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 22277967, 27091925). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Apr 11, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 20, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Jan 25, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NDUFB3 c.64T>C (p.Trp22Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 250986 control chromosomes. c.64T>C has been reported in the literature in individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 25 or related disorders. These data indicate that the variant is likely to be associated with disease. 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Oct 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Lifecell International Pvt. Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Missense variant c.64T>C in Exon 2 of the NDUFB3 gene that results in the amino acid substitution p.Trp22Arg was identified. The observed variant has a minor allele frequency of 0.00085/0.00080% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic (variant ID: 252575). This variant was reported among the patients for infantile Mitochondrial Disease (Calvo SE et al., 2012). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

not provided

Pathogenic:6

Aug 11, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NDUFB3: PP1:Moderate, PP4:Moderate, PS3:Moderate

Jun 25, 2021

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant segregates with disease and has been identified in multiple affected individuals with clinical features associated with this gene (PMID: 22277967, 22499348, 27091925). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 22277967, 22499348, 27091925). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 22 of the NDUFB3 protein (p.Trp22Arg). This variant is present in population databases (rs142609245, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22277967, 27091925). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252575). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFB3 function (PMID: 27091925). For these reasons, this variant has been classified as Pathogenic.

Jun 16, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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); This variant is associated with the following publications: (PMID: 22277967, 22499348, 27091925, 26795593, 31000363, 31589614)

Mitochondrial complex I deficiency

Pathogenic:1

Dec 17, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Jun 20, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64T>C (p.W22R) alteration is located in exon 2 (coding exon 1) of the NDUFB3 gene. This alteration results from a T to C substitution at nucleotide position 64, causing the tryptophan (W) at amino acid position 22 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.08% (239/282372) total alleles studied. The highest observed frequency was 0.14% (178/128812) of European (non-Finnish) alleles. This variant has been identified in the homozygous state or in conjunction with another NDUFB3 variant in individuals with features consistent with NDUFB3-related mitochondrial complex I deficiency; in at least one instance, the variants were identified in trans (Calvo, 2012; Haack, 2012; Alston, 2016; Hakim, 2019). This amino acid position is highly conserved in available vertebrate species. Complementation studies demonstrated that the p.W22R alteration produced decreased complex I activity (Calvo, 2012; Haack, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

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

0.0

.;T;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;.;.;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

6.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-9.3

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Vest4

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over