rs121908576

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_001371453.1(BCS1L):c.-311C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

BCS1L
NM_001371453.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 2.50

Publications

16 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
GRACILE syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
mitochondrial complex III deficiency nuclear type 1
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial complex III deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal tubulopathy-encephalopathy-liver failure syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

BCS1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.362

PP5

Variant 2-218661153-C-T is Pathogenic according to our data. Variant chr2-218661153-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371453.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCS1L	NM_001079866.2	MANE Select	c.166C>T	p.Arg56*	stop_gained	Exon 2 of 8	NP_001073335.1	Q9Y276
BCS1L	NM_001371453.1		c.-311C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001358382.1
BCS1L	NM_001371454.1		c.-311C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001358383.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCS1L	ENST00000359273.8	TSL:1 MANE Select	c.166C>T	p.Arg56*	stop_gained	Exon 2 of 8	ENSP00000352219.3	Q9Y276
BCS1L	ENST00000392109.5	TSL:1	c.166C>T	p.Arg56*	stop_gained	Exon 3 of 9	ENSP00000375957.1	Q9Y276
BCS1L	ENST00000392111.7	TSL:1	c.166C>T	p.Arg56*	stop_gained	Exon 3 of 9	ENSP00000375959.2	Q9Y276

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000167

AC:

AN:

251472

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

239

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000425

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000184

AC:

205

AN:

1112010

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000282

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00157

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000291

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Mitochondrial complex III deficiency nuclear type 1 (6)

GRACILE syndrome (3)

BCS1L-related disorder (2)

Pili torti-deafness syndrome (1)

Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C2931891:Leigh syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 (1)

Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.77

PhyloP100

2.5

Vest4

0.79

GERP RS

2.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over