2-201078894-A-G

Variant names:

• chr2-201078894-A-G
• rs750401775
• NM_002491.3:c.12A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_002491.3(NDUFB3):​c.12A>G​(p.Glu4Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,457,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NDUFB3 NM_002491.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.944
• Publications: 1 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: G2P, Ambry Genetics, 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-201078894-A-G is Benign according to our data. Variant chr2-201078894-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 511372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.944 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002491.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	NM_002491.3	MANE Select	c.12A>G	p.Glu4Glu	synonymous	Exon 2 of 3	NP_002482.1	O43676
	NDUFB3	NM_001257102.2		c.12A>G	p.Glu4Glu	synonymous	Exon 3 of 4	NP_001244031.1	O43676

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	ENST00000237889.9	TSL:1 MANE Select	c.12A>G	p.Glu4Glu	synonymous	Exon 2 of 3	ENSP00000237889.4	O43676
	NDUFB3	ENST00000433898.5	TSL:2	c.12A>G	p.Glu4Glu	synonymous	Exon 3 of 4	ENSP00000410600.1	O43676
	NDUFB3	ENST00000450023.6	TSL:3	c.12A>G	p.Glu4Glu	synonymous	Exon 2 of 3	ENSP00000401834.2	O43676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248772 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457668 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7 AN XY: 725220

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 43992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4498

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111144

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.76
PhyloP100		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs750401775; hg19: chr2-201943617;