rs200413924

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_012213.3(MLYCD):c.1424A>G(p.Lys475Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. K475I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

MLYCD
NM_012213.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.23

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

malonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

MLYCD links:

ENSG00000288849 (HGNC:):

ENSG00000288849 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044234693).

BP6

Variant 16-83915431-A-G is Benign according to our data. Variant chr16-83915431-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 320738.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLYCD	NM_012213.3 link	c.1424A>G	p.Lys475Arg	missense_variant	Exon 5 of 5	ENST00000262430.6	NP_036345.2	O95822-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLYCD	ENST00000262430.6 link	c.1424A>G	p.Lys475Arg	missense_variant	Exon 5 of 5	1	NM_012213.3	ENSP00000262430.4		O95822-1

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000521

AC:

129

AN:

247748

AF XY:

0.000519

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000973

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000811

AC:

1185

AN:

1461324

Hom.:

Cov.:

AF XY:

0.000801

AC XY:

582

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000568

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000757

AC:

AN:

52862

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000973

AC:

1082

AN:

1112010

Other (OTH)

AF:

0.000695

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000512

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41592

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000861

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000438

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase

Uncertain:1Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Uncertain:1

Mar 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MLYCD c.1424A>G (p.Lys475Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 247748 control chromosomes. To our knowledge, no occurrence of c.1424A>G in individuals affected with Deficiency Of Malonyl-CoA Decarboxylase and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1424A>G (p.K475R) alteration is located in exon 5 (coding exon 5) of the MLYCD gene. This alteration results from a A to G substitution at nucleotide position 1424, causing the lysine (K) at amino acid position 475 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

M_CAP

Benign

0.076

MetaRNN

Benign

0.044

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.0

PhyloP100

2.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.82

REVEL

Benign

0.22

Sift

Benign

0.28

Sift4G

Benign

0.35

Polyphen

0.0090

Vest4

0.048

MVP

0.96

MPC

0.017

ClinPred

0.012

GERP RS

3.7

Varity_R

0.16

gMVP

0.49

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over