16-83906979-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.529-8C>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 0.023 in 1,612,944 control chromosomes in the GnomAD database, including 1,753 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 0.065 (760 hom., cov: 33)
  • Exomes 𝑓: 0.019 (993 hom.)
• Consequence: MLYCD NM_012213.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004206
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.643

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=-0.82).
• BP6: Variant 16-83906979-C-T is Benign according to our data. Variant chr16-83906979-C-T is described in ClinVar as [Benign]. Clinvar id is 320726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-83906979-C-T is described in Lovd as [Benign]. Variant chr16-83906979-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLYCD	NM_012213.3	c.529-8C>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.529-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_012213.3	P1

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9831 AN: 152046 Hom.: 756 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.0889

Gnomad SAS AF: 0.0390

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0465

GnomAD3 exomes AF: 0.0329 AC: 8214 AN: 249570 Hom.: 387 AF XY: 0.0308 AC XY: 4164 AN XY: 135404

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.0847

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0186 AC: 27202 AN: 1460780 Hom.: 993 Cov.: 31 AF XY: 0.0186 AC XY: 13554 AN XY: 726776

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.0736

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00950

Gnomad4 OTH exome AF: 0.0329

GnomAD4 genome AF: 0.0647 AC: 9849 AN: 152164 Hom.: 760 Cov.: 33 AF XY: 0.0635 AC XY: 4722 AN XY: 74404

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.0885

Gnomad4 SAS AF: 0.0392

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0465

Alfa AF: 0.0352 Hom.: 205

Bravo AF: 0.0720

Asia WGS AF: 0.0830 AC: 291 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of malonyl-CoA decarboxylase Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.1
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs3815806; hg19: chr16-83940584;