rs555482480

Positions:

• chr16-83899651-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_012213.3(MLYCD):​c.507G>A​(p.Leu169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,541,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (0 hom.)
• Consequence: MLYCD NM_012213.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.366

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-83899651-G-A is Benign according to our data. Variant chr16-83899651-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 378148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.366 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00086 (131/152392) while in subpopulation AMR AF= 0.00209 (32/15312). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLYCD	NM_012213.3	c.507G>A	p.Leu169=	synonymous_variant	1/5	ENST00000262430.6	NP_036345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLYCD	ENST00000262430.6	c.507G>A	p.Leu169=	synonymous_variant	1/5	1	NM_012213.3	ENSP00000262430	P1

Frequencies

GnomAD3 genomes AF: 0.000860 AC: 131 AN: 152274 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00103 AC: 140 AN: 136154 Hom.: 0 AF XY: 0.00106 AC XY: 80 AN XY: 75684

Gnomad AFR exome AF: 0.000182

Gnomad AMR exome AF: 0.000964

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000962

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.000840 AC: 1167 AN: 1388956 Hom.: 0 Cov.: 30 AF XY: 0.000820 AC XY: 563 AN XY: 686676

Gnomad4 AFR exome AF: 0.000195

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00676

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.0000877

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152392 Hom.: 1 Cov.: 33 AF XY: 0.000778 AC XY: 58 AN XY: 74530

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00112

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MLYCD: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs555482480; hg19: chr16-83933256;