16-83899145-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_SupportingPM2PP5_Very_Strong

The NM_012213.3(MLYCD):c.1A>T(p.Met1?) variant causes a initiator codon 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 initiator_codon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.00

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:

ENSG00000288849 (HGNC:):

ENSG00000288849 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 40 codons. Genomic position: 83899262. Lost 0.080 part of the original CDS.

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 rank	MANE	Protein	UniProt
MLYCD	NM_012213.3 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 5	ENST00000262430.6	NP_036345.2	O95822-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MLYCD	ENST00000262430.6 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 5	1	NM_012213.3	ENSP00000262430.4	O95822-1
ENSG00000288849	ENST00000689373.1 link	n.1202-7842A>T		intron_variant	Intron 5 of 8
ENSG00000288849	ENST00000692462.1 link	n.1170-7842A>T		intron_variant	Intron 5 of 8

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149568

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

989212

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

472012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000278

Gnomad4 OTH exome

AF:

0.0000275

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149568

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72934

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MLYCD mRNA. The next in-frame methionine is located at codon 40. 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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.076

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.014

PROVEAN

Benign

-0.24

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.012

Vest4

0.89

MutPred

0.99

Loss of MoRF binding (P = 0.3341);

MVP

0.96

ClinPred

1.0

GERP RS

3.2

Varity_R

0.93

gMVP

0.53

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