chr2-74135948-C-CTTT

Variant names:

• chr2-74135948-C-CTTT
• rs55654893
• NM_212552.3:c.259-293_259-291dupAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_212552.3(BOLA3):​c.259-293_259-291dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0078 (20 hom., cov: 0)
• Consequence: BOLA3 NM_212552.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.489
• Publications: 0 publications found

Genes affected

BOLA3 (HGNC:24415): (bolA family member 3) This gene encodes a protein that plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases, and for the assembly of the mitochondrial respiratory chain complexes. Mutation in this gene has been associated with multiple mitochondrial dysfunctions syndrome-2. Two alternatively spliced transcript variants encoding different isoforms with distinct subcellular localization have been reported for this gene (PMID:21944046). [provided by RefSeq, Dec 2011]

BOLA3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple mitochondrial dysfunctions syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-74135948-C-CTTT is Benign according to our data. Variant chr2-74135948-C-CTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1220343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00776 (1045/134678) while in subpopulation AMR AF = 0.0305 (399/13076). AF 95% confidence interval is 0.028. There are 20 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212552.3. 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
	BOLA3	NM_212552.3	MANE Select	c.259-293_259-291dupAAA		intron	N/A	NP_997717.2	Q53S33-1
	BOLA3	NM_001035505.2		c.170-293_170-291dupAAA		intron	N/A	NP_001030582.1	Q53S33-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BOLA3	ENST00000327428.10	TSL:1 MANE Select	c.259-291_259-290insAAA		intron	N/A	ENSP00000331369.5	Q53S33-1
	BOLA3	ENST00000295326.4	TSL:1	c.170-291_170-290insAAA		intron	N/A	ENSP00000295326.4	Q53S33-2
	BOLA3	ENST00000477685.5	TSL:1	n.410-291_410-290insAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1043 AN: 134694 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.00165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.00242

Gnomad EAS AF: 0.000430

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00734

Gnomad OTH AF: 0.00926

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

GnomAD4 genome AF: 0.00776 AC: 1045 AN: 134678 Hom.: 20 Cov.: 0 AF XY: 0.00820 AC XY: 527 AN XY: 64298

African (AFR) AF: 0.00165 AC: 60 AN: 36362

American (AMR) AF: 0.0305 AC: 399 AN: 13076

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 8 AN: 3308

East Asian (EAS) AF: 0.000431 AC: 2 AN: 4638

South Asian (SAS) AF: 0.00170 AC: 7 AN: 4110

European-Finnish (FIN) AF: 0.0127 AC: 86 AN: 6768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00734 AC: 466 AN: 63454

Other (OTH) AF: 0.00923 AC: 17 AN: 1842

Alfa AF: 0.0153 Hom.: 183

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55654893; hg19: chr2-74363075;