rs938617354

Variant names:

• chr16-83899157-GGGCCAGGCTTGAC-G
• rs938617354
• NM_012213.3:c.22_34delTTGACGGCCAGGC

Your query was ambiguous. Multiple possible variants found:

• chr16-83899157-GGGCCAGGCTTGAC-G
• chr16-83899157-GGGCCAGGCTTGAC-GGGCCAGGCTTGACGGCCAGGCTTGAC

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_34delTTGACGGCCAGGC​(p.Leu8ValfsTer61) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,148,884 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 DEL_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. L8L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: MLYCD NM_012213.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.93
• Publications: 0 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 57 pathogenic variants in the truncated region.
• PP5: Variant 16-83899157-GGGCCAGGCTTGAC-G is Pathogenic according to our data. Variant chr16-83899157-GGGCCAGGCTTGAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2890013.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_34delTTGACGGCCAGGC	p.Leu8ValfsTer61	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_34delTTGACGGCCAGGC	p.Leu8ValfsTer61	frameshift	Exon 1 of 5	ENSP00000262430.4	O95822-1
	MLYCD	ENST00000851351.1		c.22_34delTTGACGGCCAGGC	p.Leu8ValfsTer61	frameshift	Exon 1 of 5	ENSP00000521410.1
	MLYCD	ENST00000851350.1		c.22_34delTTGACGGCCAGGC	p.Leu8ValfsTer61	frameshift	Exon 1 of 4	ENSP00000521409.1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149660 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: 0.00

Gnomad OTH AF: 0.000486

GnomAD4 exome AF: 0.00000400 AC: 4 AN: 999224 Hom.: 0 AF XY: 0.00000419 AC XY: 2 AN XY: 477508

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000459 AC: 4 AN: 870864

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

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149660 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 72998

African (AFR) AF: 0.00 AC: 0 AN: 41170

American (AMR) AF: 0.00 AC: 0 AN: 15068

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67030

Other (OTH) AF: 0.000486 AC: 1 AN: 2058

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		2.9
Mutation Taster		=15/185	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;