rs140812286

chr2-218661204-C-Gchr2-218661204-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001079866.2(BCS1L):c.217C>G(p.Arg73Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BCS1L NM_001079866.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001079866.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCS1L	NM_001079866.2	c.217C>G	p.Arg73Gly	missense_variant	2/8	ENST00000359273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCS1L	ENST00000359273.8	c.217C>G	p.Arg73Gly	missense_variant	2/8	1	NM_001079866.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 73 of the BCS1L protein (p.Arg73Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BCS1L-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;.;D;.;.;.;D;.;.;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.019	D;D;D;T;T;T;D;T;T;T;T;.
Sift4G	Uncertain	0.032	D;D;D;D;D;D;T;D;D;D;D;.
Polyphen		0.0060	.;.;.;B;B;B;.;B;B;B;B;.
Vest4		0.40, 0.41, 0.40, 0.40, 0.40, 0.40
MutPred		0.63		Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);
MVP		1.0
MPC		0.78
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs140812286; hg19: chr2-219525927;