rs121908081

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_012213.3(MLYCD):c.8G>A(p.Gly3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,146,038 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MLYCD
NM_012213.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.50

Publications

2 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: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 16-83899152-G-A is Pathogenic according to our data. Variant chr16-83899152-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4059.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLYCD	NM_012213.3 link	c.8G>A	p.Gly3Asp	missense_variant	Exon 1 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.8G>A	p.Gly3Asp	missense_variant	Exon 1 of 5	1	NM_012213.3	ENSP00000262430.4		O95822-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

149738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

8698

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

996192

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

475714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19440

American (AMR)

AF:

0.00

AC:

AN:

6086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10140

East Asian (EAS)

AF:

0.00

AC:

AN:

14452

South Asian (SAS)

AF:

0.000652

AC:

AN:

23020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2450

European-Non Finnish (NFE)

AF:

0.0000253

AC:

AN:

868792

Other (OTH)

AF:

0.000109

AC:

AN:

36688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149846

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41298

American (AMR)

AF:

0.00

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67056

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase

Pathogenic:2Uncertain:1

Jun 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3 of the MLYCD protein (p.Gly3Asp). 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 missense change has been observed in individual(s) with biochemical features of MLYCD-related disorders (PMID: 12955715; 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: 4059). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported, in one individual, as a homozygous change in patients with Malonyl-CoA decarboxylase deficiency (PMID: 12955715). Functional studies confirm this variant results in decreased mRNA levels and loss of protein function (PMID: 12955715). The c.8G>A (p.Gly3Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01150% (1/8698) and thus is presumed to be rare. The c.8G>A (p.Gly3Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.8G>A (p.Gly3Asp) variant is classified as Likely Pathogenic. -

not provided

Uncertain:1

Aug 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12955715, 23791943, 6145813) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.7

PhyloP100

1.5

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.27

REVEL

Uncertain

0.61

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.43

Vest4

0.76

MutPred

0.73

Loss of catalytic residue at G3 (P = 0.0291);

MVP

0.97

MPC

1.7

ClinPred

0.12

GERP RS

3.4

PromoterAI

0.083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.59

Mutation Taster

=32/68

disease causing

(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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rs121908081

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