rs370078811
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_012213.3(MLYCD):c.641+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,605,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
MLYCD
NM_012213.3 splice_donor_region, intron
NM_012213.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9984
2
Clinical Significance
Conservation
PhyloP100: 0.702
Genes affected
MLYCD (HGNC:7150): (malonyl-CoA decarboxylase) The product of this gene catalyzes the breakdown of malonyl-CoA to acetyl-CoA and carbon dioxide. Malonyl-CoA is an intermediate in fatty acid biosynthesis, and also inhibits the transport of fatty acyl CoAs into mitochondria. Consequently, the encoded protein acts to increase the rate of fatty acid oxidation. It is found in mitochondria, peroxisomes, and the cytoplasm. Mutations in this gene result in malonyl-CoA decarboyxlase deficiency. [provided by RefSeq, Jul 2008]
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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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLYCD | NM_012213.3 | c.641+3A>C | splice_donor_region_variant, intron_variant | ENST00000262430.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLYCD | ENST00000262430.6 | c.641+3A>C | splice_donor_region_variant, intron_variant | 1 | NM_012213.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000842 AC: 21AN: 249536Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135392
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GnomAD4 exome AF: 0.000151 AC: 219AN: 1453490Hom.: 0 Cov.: 29 AF XY: 0.000160 AC XY: 116AN XY: 723678
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Deficiency of malonyl-CoA decarboxylase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2022 | This sequence change falls in intron 2 of the MLYCD gene. It does not directly change the encoded amino acid sequence of the MLYCD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370078811, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLYCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 577880). 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at