2-201078902-A-C

Variant names:

• chr2-201078902-A-C
• rs778982161
• NM_002491.3:c.20A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002491.3(NDUFB3):​c.20A>C​(p.His7Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NDUFB3 NM_002491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Pros-methylhistidine (size 0) in uniprot entity NDUB3_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB3	NM_002491.3	c.20A>C	p.His7Pro	missense_variant	Exon 2 of 3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.20A>C	p.His7Pro	missense_variant	Exon 3 of 4		NP_001244031.1
NDUFB3	XM_011511230.4	c.20A>C	p.His7Pro	missense_variant	Exon 3 of 4		XP_011509532.1
NDUFB3	XM_047444488.1	c.20A>C	p.His7Pro	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	c.20A>C	p.His7Pro	missense_variant	Exon 2 of 3	1	NM_002491.3	ENSP00000237889.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 tolerated. This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 7 of the NDUFB3 protein (p.His7Pro). This variant is present in population databases (rs778982161, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NDUFB3-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.15	.;T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.43	T;.;.;T
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.43	T
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		0.94	.;P;P;P
Vest4		0.48
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.93
MPC		0.16
ClinPred		0.88	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.61

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: rs778982161; hg19: chr2-201943625;