rs200800978

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_StrongPP5

The NM_002491.3(NDUFB3):c.208G>T(p.Gly70*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,462 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

NDUFB3
NM_002491.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 8.47

Publications

10 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: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.3 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 2-201085526-G-T is Pathogenic according to our data. Variant chr2-201085526-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39836.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB3	NM_002491.3 link	c.208G>T	p.Gly70*	stop_gained	Exon 3 of 3	ENST00000237889.9	NP_002482.1	O43676A0A024R413
NDUFB3	NM_001257102.2 link	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		NP_001244031.1	O43676A0A024R413
NDUFB3	XM_011511230.4 link	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		XP_011509532.1	O43676A0A024R413
NDUFB3	XM_047444488.1 link	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		XP_047300444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB3	ENST00000237889.9 link	c.208G>T	p.Gly70*	stop_gained	Exon 3 of 3	1	NM_002491.3	ENSP00000237889.4		O43676

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

251020

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000160

AC:

233

AN:

1460588

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726622

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.000134

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000195

AC:

217

AN:

1111112

Other (OTH)

AF:

0.000133

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000158

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.0000657

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2110

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:

0.000142

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000657

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NDUFB3 p.Gly70* variant was identified as a compound heterozygous variant in individuals with mitochondrial complex I deficiency; functional studies in fibroblasts from this patient demonstrated low complex I activity (Haack_2012_PMID:22499348). The variant was identified in dbSNP (ID: rs200800978) and ClinVar (classified as likely pathogenic by GeneDx and as pathogenic by Ambry Genetics). The variant was identified in control databases in 31 of 282238 chromosomes at a frequency of 0.0001098 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 24 of 128702 chromosomes (freq: 0.000187), Latino in 5 of 35410 chromosomes (freq: 0.000141), Other in 1 of 7204 chromosomes (freq: 0.000139) and South Asian in 1 of 30608 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.208G>T variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function in homozygous individuals. Loss of function variants in the NDUFB3 gene are an established mechanism of disease for mitochondrial complex I deficiency and are the type of variant expected to cause the disorder when found in homozygous or compound heterozygous individuals. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly70*) in the NDUFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the NDUFB3 protein. This variant is present in population databases (rs200800978, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22499348, 26795593). ClinVar contains an entry for this variant (Variation ID: 39836). Studies have shown that this premature translational stop signal alters NDUFB3 gene expression (PMID: 22499348). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 01, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, specifically expression of NDUFB3 cDNA with either the p.W22R or p.G70X variants failed to rescue the complex I deficiency in patient fibroblasts (Haack et al., 2012); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 33233646, 26795593, 31589614, 22499348) -

Jul 02, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the NDUFB3 gene demonstrated a sequence change, c.208G>T, which results in the creation of a premature stop codon at amino acid position 70, p.Gly70*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NDUFB3 protein with potentially abnormal function. This sequence change has previously been described in a patient with isolated complex I deficiency along with another missense variant in this gene, and functional studies were performed to demonstrate pathogenicity (Haack et al., 2012). The phenotypic presentation included mitochondrial encephalopathy, mitochondrial myopathy, muscular hypotonia, developmental delay and lactic acidosis. These collective evidences indicate that this sequence change is likely pathogenic. -

Mitochondrial complex I deficiency, nuclear type 25

Pathogenic:2

Dec 26, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Aug 27, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.208G>T (p.G70*) alteration, located in exon 3 (coding exon 2) of the NDUFB3 gene, consists of a G to T substitution at nucleotide position 208. This changes the amino acid from a glycine (G) to a stop codon at amino acid position 70. This alteration occurs at the 3' terminus of the NDUFB3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29.6% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the T allele has an overall frequency of 0.011% (31/282238) total alleles studied. The highest observed frequency was 0.019% (24/128702) of European (non-Finnish) alleles. This variant has been identified in conjunction with another NDUFB3 variant in an individual with features consistent with complex I deficiency (Haack, 2012; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

not specified

Uncertain:1

May 28, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NDUFB3 c.208G>T (p.Gly70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein and not involved in nonsense mediated decay. The variant allele was found at a frequency of 0.00012 in 251020 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NDUFB3 causing Mitochondrial Complex 1 Deficiency, Nuclear Type 25, allowing no conclusion about variant significance. c.208G>T has been observed in individuals with clinical features of Mitochondrial Complex 1 Deficiency (Haack_2012, Helbig_2016, Riquin_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected activity and protein expression of mitochondrial complex I in the patients fibroblasts (Haack_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22499348, 26795593, 34354612, 37614113, 38999368). ClinVar contains an entry for this variant (Variation ID: 39836). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.5

Vest4

0.49

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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