rs146465073

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM2PM5BP4_ModerateBP6BS1

The NM_012213.3(MLYCD):​c.929G>A​(p.Arg310Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00051 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

MLYCD
NM_012213.3 missense

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.93
Variant links:
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-83912348-G-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.24199498).
BP6
Variant 16-83912348-G-A is Benign according to our data. Variant chr16-83912348-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1014754.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000512 (78/152282) while in subpopulation AFR AF= 0.00166 (69/41550). AF 95% confidence interval is 0.00135. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MLYCDNM_012213.3 linkuse as main transcriptc.929G>A p.Arg310Gln missense_variant 4/5 ENST00000262430.6 NP_036345.2 O95822-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLYCDENST00000262430.6 linkuse as main transcriptc.929G>A p.Arg310Gln missense_variant 4/51 NM_012213.3 ENSP00000262430.4 O95822-1

Frequencies

GnomAD3 genomes
AF:
0.000447
AC:
68
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00142
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000100
AC:
25
AN:
249494
Hom.:
0
AF XY:
0.0000739
AC XY:
10
AN XY:
135384
show subpopulations
Gnomad AFR exome
AF:
0.00142
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000848
AC:
124
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.0000784
AC XY:
57
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00203
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000512
AC:
78
AN:
152282
Hom.:
1
Cov.:
32
AF XY:
0.000497
AC XY:
37
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00166
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.0000652
Hom.:
0
Bravo
AF:
0.000468
ESP6500AA
AF:
0.00170
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000140
AC:
17
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 09, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 31, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T
Eigen
Benign
0.10
Eigen_PC
Benign
0.023
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.88
D
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.24
T
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
1.5
L
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.44
Sift
Benign
0.091
T
Sift4G
Uncertain
0.020
D
Polyphen
0.97
D
Vest4
0.77
MVP
0.97
MPC
0.070
ClinPred
0.059
T
GERP RS
4.3
Varity_R
0.42
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146465073; hg19: chr16-83945953; COSMIC: COSV105865744; API