chr2-201079018-G-A

Variant names:

• chr2-201079018-G-A
• rs1575544444
• NM_002491.3:c.136G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002491.3(NDUFB3):​c.136G>A​(p.Gly46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFB3 NM_002491.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.79
• 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: 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: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3473165).

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.136G>A	p.Gly46Ser	missense	Exon 2 of 3	NP_002482.1	O43676
	NDUFB3	NM_001257102.2		c.136G>A	p.Gly46Ser	missense	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.136G>A	p.Gly46Ser	missense	Exon 2 of 3	ENSP00000237889.4	O43676
	NDUFB3	ENST00000433898.5	TSL:2	c.136G>A	p.Gly46Ser	missense	Exon 3 of 4	ENSP00000410600.1	O43676
	NDUFB3	ENST00000450023.6	TSL:3	c.136G>A	p.Gly46Ser	missense	Exon 2 of 3	ENSP00000401834.2	O43676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454990 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723858

African (AFR) AF: 0.0000303 AC: 1 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 42246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 84636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110372

Other (OTH) AF: 0.0000166 AC: 1 AN: 60102

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental cataract;C0036572:Seizure;C1836830:Developmental regression;C1843392:Death in childhood (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.68	T
PhyloP100		2.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.20
Sift	Benign	0.099	T
Sift4G	Benign	0.43	T
Polyphen		0.70	P
Vest4		0.39
MutPred		0.35		Gain of glycosylation at P44 (P = 0.0758)
MVP		0.84
MPC		0.44
ClinPred		0.97	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.42
gMVP		0.67
Mutation Taster		=73/27	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: rs1575544444; hg19: chr2-201943741;