rs776641008
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_020166.5(MCCC1):c.1973_1977+28del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
MCCC1
NM_020166.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
NM_020166.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.488
Genes affected
MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.04912764 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of -27, new splice context is: tctGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP5
?
Variant 3-183020101-ACATCATTCTACAGATGTCATGTGATTACCTTTT-A is Pathogenic according to our data. Variant chr3-183020101-ACATCATTCTACAGATGTCATGTGATTACCTTTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 498130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.1973_1977+28del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 17/19 | ENST00000265594.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.1973_1977+28del | splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant | 17/19 | 1 | NM_020166.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250084Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135182
GnomAD3 exomes
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250084
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AN XY:
135182
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 27, 2016 | - - |
3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This variant results in the deletion of the last 5 nucleotides of exon 17 and affects a donor splice site in intron 17 of the MCCC1 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 MCCC1 are known to be pathogenic (PMID: 11181649, 15359379, 22642865). This variant is present in population databases (rs776641008, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MCCC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498130). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at