chr16-83899157-G-GGGCCAGGCTTGAC

Variant names:

• chr16-83899157-G-GGGCCAGGCTTGAC
• rs938617354
• NM_012213.3:c.22_34dupTTGACGGCCAGGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_012213.3(MLYCD):​c.22_34dupTTGACGGCCAGGC​(p.Arg12LeufsTer200) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,148,992 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R12R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: MLYCD NM_012213.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.87
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• malonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ENSG00000288849 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
• PP5: Variant 16-83899157-G-GGGCCAGGCTTGAC is Pathogenic according to our data. Variant chr16-83899157-G-GGGCCAGGCTTGAC is described in ClinVar as Pathogenic. ClinVar VariationId is 1400055.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012213.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLYCD	NM_012213.3	MANE Select	c.22_34dupTTGACGGCCAGGC	p.Arg12LeufsTer200	frameshift	Exon 1 of 5	NP_036345.2	O95822-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLYCD	ENST00000262430.6	TSL:1 MANE Select	c.22_34dupTTGACGGCCAGGC	p.Arg12LeufsTer200	frameshift	Exon 1 of 5	ENSP00000262430.4	O95822-1
	MLYCD	ENST00000851351.1		c.22_34dupTTGACGGCCAGGC	p.Arg12LeufsTer209	frameshift	Exon 1 of 5	ENSP00000521410.1
	MLYCD	ENST00000851350.1		c.22_34dupTTGACGGCCAGGC	p.Arg12LeufsTer200	frameshift	Exon 1 of 4	ENSP00000521409.1

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149660 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000500 AC: 5 AN: 999224 Hom.: 0 Cov.: 28 AF XY: 0.0000105 AC XY: 5 AN XY: 477508

African (AFR) AF: 0.000205 AC: 4 AN: 19526

American (AMR) AF: 0.00 AC: 0 AN: 6154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10256

East Asian (EAS) AF: 0.0000682 AC: 1 AN: 14658

South Asian (SAS) AF: 0.00 AC: 0 AN: 23096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 870864

Other (OTH) AF: 0.00 AC: 0 AN: 36860

GnomAD4 genome AF: 0.0000334 AC: 5 AN: 149768 Hom.: 0 Cov.: 33 AF XY: 0.0000547 AC XY: 4 AN XY: 73116

African (AFR) AF: 0.000121 AC: 5 AN: 41288

American (AMR) AF: 0.00 AC: 0 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67020

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Deficiency of malonyl-CoA decarboxylase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=20/180	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs938617354; hg19: chr16-83932762;