chr2-201077757-G-A

Variant names:

• chr2-201077757-G-A
• rs10194347
• NM_002491.3:c.-2-1124G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002491.3(NDUFB3):​c.-2-1124G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 151,966 control chromosomes in the GnomAD database, including 2,401 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2401 hom., cov: 32)
• Consequence: NDUFB3 NM_002491.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	NM_002491.3	MANE Select	c.-2-1124G>A		intron	N/A	NP_002482.1
	NDUFB3	NM_001257102.2		c.-2-1124G>A		intron	N/A	NP_001244031.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	ENST00000237889.9	TSL:1 MANE Select	c.-2-1124G>A		intron	N/A	ENSP00000237889.4
	NDUFB3	ENST00000433898.5	TSL:2	c.-2-1124G>A		intron	N/A	ENSP00000410600.1
	NDUFB3	ENST00000450023.6	TSL:3	c.-2-1124G>A		intron	N/A	ENSP00000401834.2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25803 AN: 151848 Hom.: 2395 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.170 AC: 25831 AN: 151966 Hom.: 2401 Cov.: 32 AF XY: 0.167 AC XY: 12404 AN XY: 74294

African (AFR) AF: 0.211 AC: 8735 AN: 41426

American (AMR) AF: 0.144 AC: 2204 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 744 AN: 3468

East Asian (EAS) AF: 0.00829 AC: 43 AN: 5184

South Asian (SAS) AF: 0.0703 AC: 338 AN: 4806

European-Finnish (FIN) AF: 0.165 AC: 1747 AN: 10558

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11499 AN: 67960

Other (OTH) AF: 0.172 AC: 362 AN: 2104

Alfa AF: 0.169 Hom.: 7140

Bravo AF: 0.172

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.49
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs10194347; hg19: chr2-201942480;