rs121908081

Variant names:

• chr16-83899152-G-A
• rs121908081
• NM_012213.3:c.8G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-83899152-G-A
• chr16-83899152-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_012213.3(MLYCD):​c.8G>A​(p.Gly3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,146,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MLYCD NM_012213.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.50
• Publications: 2 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, Orphanet, PanelApp Australia, G2P

ENSG00000288849 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 16-83899152-G-A is Pathogenic according to our data. Variant chr16-83899152-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4059.

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.8G>A	p.Gly3Asp	missense	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.8G>A	p.Gly3Asp	missense	Exon 1 of 5	ENSP00000262430.4	O95822-1
	MLYCD	ENST00000851351.1		c.8G>A	p.Gly3Asp	missense	Exon 1 of 5	ENSP00000521410.1
	MLYCD	ENST00000851350.1		c.8G>A	p.Gly3Asp	missense	Exon 1 of 4	ENSP00000521409.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 149738 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: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 1 AN: 8698 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 41 AN: 996192 Hom.: 0 Cov.: 28 AF XY: 0.0000441 AC XY: 21 AN XY: 475714

African (AFR) AF: 0.00 AC: 0 AN: 19440

American (AMR) AF: 0.00 AC: 0 AN: 6086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10140

East Asian (EAS) AF: 0.00 AC: 0 AN: 14452

South Asian (SAS) AF: 0.000652 AC: 15 AN: 23020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2450

European-Non Finnish (NFE) AF: 0.0000253 AC: 22 AN: 868792

Other (OTH) AF: 0.000109 AC: 4 AN: 36688

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 149846 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73134

African (AFR) AF: 0.00 AC: 0 AN: 41298

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67056

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Deficiency of malonyl-CoA decarboxylase (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.61
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.43	B
Vest4		0.76
MutPred		0.73		Loss of catalytic residue at G3 (P = 0.0291)
MVP		0.97
MPC		1.7
ClinPred		0.12	T
GERP RS		3.4
PromoterAI		0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.59
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs121908081; hg19: chr16-83932757;