chr16-83899145-A-T

Position:

• chr16-83899145-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_012213.3(MLYCD):​c.1A>T​(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 0.0000228 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 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_012213.3 (MLYCD) was described as [Likely_pathogenic] in ClinVar as 2634044
• 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/exons	MANE	UniProt
MLYCD	NM_012213.3	c.1A>T	p.Met1?	start_lost	1/5	ENST00000262430.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLYCD	ENST00000262430.6	c.1A>T	p.Met1?	start_lost	1/5	1	NM_012213.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149568 Hom.: 0 Cov.: 33

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: 25 AN: 989212 Hom.: 0 Cov.: 28 AF XY: 0.0000360 AC XY: 17 AN XY: 472012

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: 1 AN: 149568 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 72934

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

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	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: 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	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.014	D
MutationTaster	Benign	0.84	N
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.012	B
Vest4		0.89
MutPred		0.99		Loss of MoRF binding (P = 0.3341);
MVP		0.96
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs1179555424; hg19: chr16-83932750;