NM_001079866.2:c.-50+541G>A

Variant names:

• chr2-218660284-G-A
• rs3806556
• NM_001079866.2:c.-50+541G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001079866.2(BCS1L):​c.-50+541G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 152,592 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.056 (333 hom., cov: 32)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: BCS1L NM_001079866.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.215
• Publications: 3 publications found

Genes affected

BCS1L (HGNC:1020): (BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone) This gene encodes a homolog of the S. cerevisiae bcs1 protein which is involved in the assembly of complex III of the mitochondrial respiratory chain. The encoded protein does not contain a mitochondrial targeting sequence but experimental studies confirm that it is imported into mitochondria. Mutations in this gene are associated with mitochondrial complex III deficiency and the GRACILE syndrome. Several alternatively spliced transcripts encoding two different isoforms have been described. [provided by RefSeq, Jan 2016]

BCS1L Gene-Disease associations (from GenCC):

• Bjornstad syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• GRACILE syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, ClinGen
• mitochondrial complex III deficiency nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal tubulopathy-encephalopathy-liver failure syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-218660284-G-A is Benign according to our data. Variant chr2-218660284-G-A is described in ClinVar as Benign. ClinVar VariationId is 673726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079866.2. 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
	BCS1L	NM_001079866.2	MANE Select	c.-50+541G>A		intron	N/A	NP_001073335.1	Q9Y276
	BCS1L	NM_001371444.1		c.-187G>A		5_prime_UTR	Exon 2 of 9	NP_001358373.1	Q9Y276
	BCS1L	NM_001371446.1		c.-514G>A		5_prime_UTR	Exon 1 of 8	NP_001358375.1	A0A024R445

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.-50+541G>A		intron	N/A	ENSP00000352219.3	Q9Y276
	BCS1L	ENST00000392109.5	TSL:1	c.-50+66G>A		intron	N/A	ENSP00000375957.1	Q9Y276
	BCS1L	ENST00000392111.7	TSL:1	c.-50+39G>A		intron	N/A	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8471 AN: 152130 Hom.: 332 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0504

GnomAD4 exome AF: 0.0203 AC: 7 AN: 344 Hom.: 0 Cov.: 0 AF XY: 0.0253 AC XY: 5 AN XY: 198

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0177 AC: 5 AN: 282

Other (OTH) AF: 0.00 AC: 0 AN: 16

GnomAD4 genome AF: 0.0557 AC: 8485 AN: 152248 Hom.: 333 Cov.: 32 AF XY: 0.0547 AC XY: 4073 AN XY: 74452

African (AFR) AF: 0.104 AC: 4332 AN: 41528

American (AMR) AF: 0.0311 AC: 476 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3472

East Asian (EAS) AF: 0.119 AC: 617 AN: 5182

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4830

European-Finnish (FIN) AF: 0.0272 AC: 289 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0339 AC: 2303 AN: 68022

Other (OTH) AF: 0.0499 AC: 105 AN: 2106

Alfa AF: 0.0434 Hom.: 40

Bravo AF: 0.0585

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GRACILE syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.67
PhyloP100		0.21
BranchPoint Hunter		2.0
PromoterAI		-0.012	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 23

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

Other links and lift over

dbSNP: rs3806556; hg19: chr2-219525007;