rs138794621
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_020166.5(MCCC1):c.873G>A(p.Ala291Ala) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000282 in 1,597,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 1 hom. )
Consequence
MCCC1
NM_020166.5 splice_region, synonymous
NM_020166.5 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.72
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 4: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF, Dann was below the threshold]
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.873G>A | p.Ala291Ala | splice_region_variant, synonymous_variant | 8/19 | ENST00000265594.9 | NP_064551.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.873G>A | p.Ala291Ala | splice_region_variant, synonymous_variant | 8/19 | 1 | NM_020166.5 | ENSP00000265594.4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
7
AN:
152140
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000262 AC: 6AN: 228920Hom.: 0 AF XY: 0.0000163 AC XY: 2AN XY: 123012
GnomAD3 exomes
AF:
AC:
6
AN:
228920
Hom.:
AF XY:
AC XY:
2
AN XY:
123012
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000263 AC: 38AN: 1445464Hom.: 1 Cov.: 30 AF XY: 0.0000265 AC XY: 19AN XY: 717510
GnomAD4 exome
AF:
AC:
38
AN:
1445464
Hom.:
Cov.:
30
AF XY:
AC XY:
19
AN XY:
717510
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
GnomAD4 genome
AF:
AC:
7
AN:
152140
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74334
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylcrotonyl-CoA carboxylase deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2021 | The c.873G>A (p.A291A) alteration is located in exon 8 (coding exon 8) of the MCCC1 gene. This alteration consists of a G to A substitution at nucleotide position 873. This nucleotide substitution does not change the alanine at codon 291. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 25, 2018 | - - |
3-methylcrotonyl-CoA carboxylase 1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 14, 2022 | This sequence change affects codon 291 of the MCCC1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MCCC1 protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs138794621, gnomAD 0.02%). This variant has been observed in individual(s) with MCCC1-related conditions (PMID: 30626930). ClinVar contains an entry for this variant (Variation ID: 167271). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -23
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at