2-201078708-A-G

Variant names:

• chr2-201078708-A-G
• rs11887751
• NM_002491.3:c.-2-173A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002491.3(NDUFB3):​c.-2-173A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 152,080 control chromosomes in the GnomAD database, including 472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.052 (472 hom., cov: 32)
• Consequence: NDUFB3 NM_002491.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.401
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-201078708-A-G is Benign according to our data. Variant chr2-201078708-A-G is described in ClinVar as Benign. ClinVar VariationId is 675479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFB3	NM_002491.3	MANE Select	c.-2-173A>G		intron	N/A	NP_002482.1	O43676
	NDUFB3	NM_001257102.2		c.-2-173A>G		intron	N/A	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.-2-173A>G		intron	N/A	ENSP00000237889.4	O43676
	NDUFB3	ENST00000878932.1		c.-175A>G		5_prime_UTR	Exon 1 of 2	ENSP00000548991.1
	NDUFB3	ENST00000433898.5	TSL:2	c.-2-173A>G		intron	N/A	ENSP00000410600.1	O43676

Frequencies

GnomAD3 genomes AF: 0.0518 AC: 7876 AN: 151968 Hom.: 469 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0445

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

GnomAD4 genome AF: 0.0519 AC: 7890 AN: 152080 Hom.: 472 Cov.: 32 AF XY: 0.0514 AC XY: 3825 AN XY: 74354

African (AFR) AF: 0.144 AC: 5984 AN: 41506

American (AMR) AF: 0.0202 AC: 308 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4818

European-Finnish (FIN) AF: 0.0158 AC: 166 AN: 10524

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0171 AC: 1161 AN: 68002

Other (OTH) AF: 0.0441 AC: 93 AN: 2108

Alfa AF: 0.0226 Hom.: 105

Bravo AF: 0.0560

Asia WGS AF: 0.0140 AC: 50 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.57
PhyloP100		0.40
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: rs11887751; hg19: chr2-201943431;