rs2278037

chr16-83908121-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012213.3(MLYCD):c.642-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,613,708 control chromosomes in the GnomAD database, including 3,127 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (477 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2650 hom.)
• Consequence: MLYCD NM_012213.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001181
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.97

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-83908121-C-T is Benign according to our data. Variant chr16-83908121-C-T is described in ClinVar as [Benign]. Clinvar id is 95503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-83908121-C-T is described in Lovd as [Benign]. Variant chr16-83908121-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLYCD	NM_012213.3	c.642-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262430.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLYCD	ENST00000262430.6	c.642-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012213.3	P1
MLYCD	ENST00000561562.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11031 AN: 152122 Hom.: 471 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0643 AC: 16027 AN: 249438 Hom.: 699 AF XY: 0.0583 AC XY: 7896 AN XY: 135336

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.0174

Gnomad FIN exome AF: 0.0634

Gnomad NFE exome AF: 0.0491

Gnomad OTH exome AF: 0.0591

GnomAD4 exome AF: 0.0538 AC: 78647 AN: 1461468 Hom.: 2650 Cov.: 32 AF XY: 0.0519 AC XY: 37716 AN XY: 727030

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.0649

Gnomad4 NFE exome AF: 0.0499

Gnomad4 OTH exome AF: 0.0508

GnomAD4 genome AF: 0.0727 AC: 11062 AN: 152240 Hom.: 477 Cov.: 33 AF XY: 0.0737 AC XY: 5483 AN XY: 74440

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.0515

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0509 Hom.: 517

Bravo AF: 0.0780

Asia WGS AF: 0.0790 AC: 273 AN: 3478

EpiCase AF: 0.0419

EpiControl AF: 0.0436

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.0070
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs2278037; hg19: chr16-83941726; COSMIC: COSV52306069; COSMIC: COSV52306069;