Variant 16-83899146-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_012213.3(MLYCD):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 990,390 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

MLYCD
NM_012213.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.70

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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 16-83899146-T-C is Pathogenic according to our data. Variant chr16-83899146-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2705148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLYCD	NM_012213.3 link	c.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 5	1	NM_012213.3	ENSP00000262430.4	O95822-1
ENSG00000288849	ENST00000689373.1 link	n.1202-7841T>C		intron_variant	Intron 5 of 8
ENSG00000288849	ENST00000692462.1 link	n.1170-7841T>C		intron_variant	Intron 5 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000202

AC:

AN:

990390

Hom.:

Cov.:

AF XY:

0.00000212

AC XY:

AN XY:

472640

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:

0.00000231

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase

Pathogenic:1

Dec 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the MLYCD mRNA. The next in-frame methionine is located at codon 40. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with biochemical features of MLYCD-related disorders (PMID: 24613099, 32602666; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects MLYCD function (PMID: 24613099). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.090

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.14

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.12

Vest4

0.90

MutPred

0.98

Gain of phosphorylation at M1 (P = 0.0101);

MVP

0.97

ClinPred

1.0

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.94

gMVP

0.69

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