chr2-201078946-T-C

Position:

• chr2-201078946-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 252575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201078946-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFB3	NM_002491.3	c.64T>C	p.Trp22Arg	missense_variant	2/3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.64T>C	p.Trp22Arg	missense_variant	3/4		NP_001244031.1
NDUFB3	XM_011511230.4	c.64T>C	p.Trp22Arg	missense_variant	3/4		XP_011509532.1
NDUFB3	XM_047444488.1	c.64T>C	p.Trp22Arg	missense_variant	3/4		XP_047300444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFB3	ENST00000237889.9	c.64T>C	p.Trp22Arg	missense_variant	2/3	1	NM_002491.3	ENSP00000237889	P1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152056 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000853 AC: 214 AN: 250986 Hom.: 0 AF XY: 0.000929 AC XY: 126 AN XY: 135644

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 SAS exome AF: 0.000621

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.: 0 Cov.: 31 AF XY: 0.00171 AC XY: 1240 AN XY: 726856

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74388

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.00136

EpiControl AF: 0.00172

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 25 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 25, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 21, 2021	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2022	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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	NDUFB3: PP1:Moderate, PP4:Moderate, PS3:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2021	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. -

Mitochondrial complex I deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 17, 2015

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2021

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 mutation was reported homozygous in an individual with severe intrauterine growth restriction, failure to thrive, hypotonia, and recurrent episodes of metabolic acidosis (Calvo, 2012). It was also identified compound heterozygous with a nonsense variant in an individual with hypotonia, developmental delay, and lactic acidosis (Haack, 2012). Another study of 8 families with individuals homozygous for this variant showed a distinctive facial appearance, short stature, and a more mild biochemical and clinical phenotype, although some patients presented with acute metabolic crises (Alston, 2016). 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	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;.;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
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
Polyphen		1.0	.;D;D;D
Vest4		0.98
MutPred		0.73		Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);
MVP		0.97
MPC		0.38
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs142609245; hg19: chr2-201943669;