16-83899145-A-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_012213.3(MLYCD):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,138,780 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
MLYCD
NM_012213.3 start_lost
NM_012213.3 start_lost
Scores
6
4
6
Clinical Significance
Conservation
PhyloP100: 2.00
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-83899145-A-T is Pathogenic according to our data. Variant chr16-83899145-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 847051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLYCD | NM_012213.3 | c.1A>T | p.Met1? | start_lost | 1/5 | ENST00000262430.6 | NP_036345.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLYCD | ENST00000262430.6 | c.1A>T | p.Met1? | start_lost | 1/5 | 1 | NM_012213.3 | ENSP00000262430 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000669 AC: 1AN: 149568Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000253 AC: 25AN: 989212Hom.: 0 Cov.: 28 AF XY: 0.0000360 AC XY: 17AN XY: 472012
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GnomAD4 genome AF: 0.00000669 AC: 1AN: 149568Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1AN XY: 72934
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of malonyl-CoA decarboxylase Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 03, 2023 | This sequence change affects the initiator methionine of the MLYCD mRNA. The next in-frame methionine is located at codon 40. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with biochemical features of MLYCD-related disorders (PMID: 32602666; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 847051). Studies have shown that disruption of the initiator codon alters MLYCD gene expression (PMID: 12955715). This variant disrupts a region of the MLYCD protein in which other variant(s) (p.G3D) have been observed in individuals with MLYCD-related conditions (PMID: 12955715). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
N
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
B
Vest4
MutPred
Loss of MoRF binding (P = 0.3341);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at