chr2-201078957-A-C

Variant names:

• chr2-201078957-A-C
• NM_002491.3:c.75A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002491.3(NDUFB3):​c.75A>C​(p.Glu25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFB3 NM_002491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 2 ACMG points.

• 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.75A>C	p.Glu25Asp	missense_variant	Exon 2 of 3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.75A>C	p.Glu25Asp	missense_variant	Exon 3 of 4		NP_001244031.1
NDUFB3	XM_011511230.4	c.75A>C	p.Glu25Asp	missense_variant	Exon 3 of 4		XP_011509532.1
NDUFB3	XM_047444488.1	c.75A>C	p.Glu25Asp	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.75A>C	p.Glu25Asp	missense_variant	Exon 2 of 3	1	NM_002491.3	ENSP00000237889.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461316 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 05, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;T;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.076	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.059	T;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		1.0	.;D;D;D
Vest4		0.29
MutPred		0.71		Loss of ubiquitination at K23 (P = 0.0618);Loss of ubiquitination at K23 (P = 0.0618);Loss of ubiquitination at K23 (P = 0.0618);Loss of ubiquitination at K23 (P = 0.0618);
MVP		0.79
MPC		0.36
ClinPred		0.98	D
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.43
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-201943680;