2-201079021-C-A

Variant names:

• chr2-201079021-C-A
• rs772960455
• NM_002491.3:c.139C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002491.3(NDUFB3):​c.139C>A​(p.Arg47Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB3 NM_002491.3 missense, splice_region
• Scores: Splicing: ADA: 0.6652
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB3	NM_002491.3	c.139C>A	p.Arg47Ser	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.139C>A	p.Arg47Ser	missense_variant, splice_region_variant	Exon 3 of 4		NP_001244031.1
NDUFB3	XM_011511230.4	c.139C>A	p.Arg47Ser	missense_variant, splice_region_variant	Exon 3 of 4		XP_011509532.1
NDUFB3	XM_047444488.1	c.139C>A	p.Arg47Ser	missense_variant, splice_region_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.139C>A	p.Arg47Ser	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_002491.3	ENSP00000237889.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>A (p.R47S) alteration is located in exon 2 (coding exon 1) of the NDUFB3 gene. This alteration results from a C to A substitution at nucleotide position 139, causing the arginine (R) at amino acid position 47 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.48	D
PhyloP100		3.8
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.086	T;T;T;T
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.93
MutPred		0.69		Loss of MoRF binding (P = 0.0397);Loss of MoRF binding (P = 0.0397);Loss of MoRF binding (P = 0.0397);Loss of MoRF binding (P = 0.0397);
MVP		0.98
MPC		0.14
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.92
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.47
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

Other links and lift over

dbSNP: rs772960455; hg19: chr2-201943744;