chr2-218661308-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_001079866.2(BCS1L):βc.320+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Consequence
NM_001079866.2 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCS1L | NM_001079866.2 | c.320+1G>T | splice_donor_variant | ENST00000359273.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCS1L | ENST00000359273.8 | c.320+1G>T | splice_donor_variant | 1 | NM_001079866.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250504Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000316 AC XY: 23AN XY: 727238
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
GRACILE syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 12, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2022 | Variant summary: BCS1L c.320+1G>T alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250504 control chromosomes. c.320+1G>T has been reported in the literature in individuals affected with GRACILE Syndrome (example, Visapaa_2002) and Bjornstad Syndrome (example, Hinson_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2019 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 12215968, 17314340, 25895478) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change affects a donor splice site in intron 3 of the BCS1L gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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 (rs386833856, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome and Bjββrnstad syndrome (PMID: 12215968, 17314340). This variant is also known as 321G>T and IVS2+1G>T. ClinVar contains an entry for this variant (Variation ID: 56412). 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. - |
Pili torti-deafness syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 04, 2023 | - - |
Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 24, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2020 | The c.320+1G>T intronic variant results from a G to T substitution one nucleotide after exon 3 (coding exon 1) of the BCS1L gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to disrupt the methionine residue at the initiation codon (ATG) or cause a shift in the mRNA reading frame; however, direct evidence is unavailable. This alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017), and would impact the first 120 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the BCS1L c.320+1G>T alteration was observed in 0.0012% (3/250504) of total alleles studied. This alteration has been reported in an individual with GRACILE syndrome (Visapää, 2002) and in trans with another alteration in BCSL1 in an individual with Björnstad syndrome (Hinson, 2007). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at