chr16-83899157-G-A

Position:

chr16-83899157-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_012213.3(MLYCD):c.13G>A(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,148,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

MLYCD
NM_012213.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.159

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]

MLYCD links:

Genome browser will be placed here

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;

BP4

Computational evidence support a benign effect (MetaRNN=0.004541695).

BP6

Variant 16-83899157-G-A is Benign according to our data. Variant chr16-83899157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 320720.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLYCD	NM_012213.3 linkuse as main transcript	c.13G>A	p.Gly5Arg	missense_variant	1/5	ENST00000262430.6	NP_036345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLYCD	ENST00000262430.6 linkuse as main transcript	c.13G>A	p.Gly5Arg	missense_variant	1/5	1	NM_012213.3	ENSP00000262430	P1	O95822-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

149660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000664

Gnomad ASJ

AF:

0.00612

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000492

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000644

AC:

AN:

9312

Hom.:

AF XY:

0.000827

AC XY:

AN XY:

6046

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00349

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.000514

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000471

AC:

471

AN:

999224

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

222

AN XY:

477508

show subpopulations

Gnomad4 AFR exome

AF:

0.0000512

Gnomad4 AMR exome

AF:

0.000325

Gnomad4 ASJ exome

AF:

0.00507

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000195

Gnomad4 NFE exome

AF:

0.000448

Gnomad4 OTH exome

AF:

0.000624

GnomAD4 genome

AF:

0.000388

AC:

AN:

149660

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

AN XY:

72998

show subpopulations

Gnomad4 AFR

AF:

0.0000729

Gnomad4 AMR

AF:

0.0000664

Gnomad4 ASJ

AF:

0.00612

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000492

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.000344

ExAC

AF:

0.000265

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 5 of the MLYCD protein (p.Gly5Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 320720). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MLYCD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.14

CADD

Benign

8.5

DANN

Benign

0.89

DEOGEN2

Benign

0.077

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.13

REVEL

Benign

0.14

Sift

Benign

0.54

Sift4G

Benign

0.58

Polyphen

0.0080

Vest4

0.20

MutPred

0.28

Gain of methylation at G5 (P = 0.0026);

MVP

0.91

MPC

1.4

ClinPred

0.035

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.033

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over