rs121908576
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001371453.1(BCS1L):βc.-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 (β β ).
Frequency
Consequence
NM_001371453.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BCS1L | NM_001079866.2 | c.166C>T | p.Arg56* | stop_gained | Exon 2 of 8 | ENST00000359273.8 | NP_001073335.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000167 AC: 42AN: 251472Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135914
GnomAD4 exome AF: 0.000163 AC: 239AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.000147 AC XY: 107AN XY: 727248
GnomAD4 genome AF: 0.000282 AC: 43AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74468
ClinVar
Submissions by phenotype
Mitochondrial complex III deficiency nuclear type 1 Pathogenic:6
- -
- -
ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 strong, PM3 moderate, PP1 supporting -
- -
The c.166C>T;p.Arg56* variant creates a premature translational stop signal in the BCS1L gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6169; PMID: 12215968, PMID:12910490, PMID:19508421, PMID:22277166) - PS4. The variant is present at low allele frequencies population databases (rs121908576 β gnomAD 0.001626%; ABraOM 0.000854 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bjornstad syndrome (MIM#262000), GRACILE syndrome (MIM#603358) and mitochondrial complex III deficiency, nuclear type (MIM#1124000). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (46 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in a compound heterozygous state in multiple individuals with mitochondrial complex III deficiency or GRACILE syndrome (ClinVar, PMID: 19508421, PMID: 12215968). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:6
- -
- -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22277166, 34662929, 19389488, 30634555, 30582773, 31214239, 26990548, 28496993, 31589614, 28128857, 31345219, 38256023, 37236975, 12215968, 34650211, 31435670, 12910490, 20518024, 19508421) -
BCS1L: PVS1, PS4:Moderate -
This sequence change creates a premature translational stop signal (p.Arg56*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs121908576, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with BCS1L-related conditions (PMID: 12215968, 12910490, 19508421, 22277166). ClinVar contains an entry for this variant (Variation ID: 6169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
- -
GRACILE syndrome Pathogenic:3
Variant summary: The BCS1L c.166C>T (p.Arg56X) variant results in a premature termination codon, predicted to cause a truncated or absent BCS1L protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. The variant is predicted to truncate N-terminal, P-loop and ATPase domains. Truncations downstream of this position (e.g. p.R186* and p.R291*, etc.) have been have been reported in patients with BCS1L-linked phenotypes in literature. Functional study shows that this variant drastically reduces the expression of mRNA (Gil-Borlado_2009). This variant was found in 23/122068 control chromosomes at a frequency of 0.0001884, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCS1L variant (0.0025). This variant is found in several families/patients with complex III deficiency in compound heterozygous with other missense or promoter mutations. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
- -
NM_004328.4(BCS1L):c.166C>T(R56*) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12910490, 12215968, 22277166 and 20518024. Classification of NM_004328.4(BCS1L):c.166C>T(R56*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
BCS1L-related disorder Pathogenic:2
The BCS1L c.166C>T (p.Arg56Ter) variant is a stop-gained variant which is predicted to truncate the protein. The p.Arg56Ter variant has been reported in at least five studies in a total of six individuals with mitochondrial respiratory chain complex III deficiency or GRACILE syndrome, including an affected sibling pair, in a compound heterozygous state (Visapaa et al. 2002; De Meirleir et al. 2003; Gil-Borlado et al. 2009; Ramos-Arroyo et al. 2009; Lynn et al. 2012). The variant was also found in a heterozygous state in an unaffected parent of the affected sibling pair who exhibited isolated biochemical complex III deficiency in the liver (De Meirleir et al. 2003). The p.Arg56Ter variant was absent from 400 controls, and is reported at a frequency of 0.00069 in the Latino population of the Exome Aggregation Consortium. Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Arg56Ter variant is classified as pathogenic for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
The BCS1L c.166C>T variant is predicted to result in premature protein termination (p.Arg56*). This variant was reported as pathogenic in multiple individuals with autosomal recessive GRACILE syndrome or mitochondrial complex 3 deficiency (Visapaa. 2002. PubMed ID: 12215968; MorΓ‘n. 2010. PubMed ID: 20518024; Lynn. 2012. PubMed ID: 22277166). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in BCS1L are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pili torti-deafness syndrome Pathogenic:1
- -
Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C2931891:Leigh syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
- -
Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at