16-83915051-G-T

Variant names:

• chr16-83915051-G-T
• rs138675420
• NM_012213.3:c.1044G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012213.3(MLYCD):​c.1044G>T​(p.Glu348Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,250 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: MLYCD NM_012213.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -1.43
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052485764).
• BP6: Variant 16-83915051-G-T is Benign according to our data. Variant chr16-83915051-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 320731.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.1044G>T	p.Glu348Asp	missense	Exon 5 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.1044G>T	p.Glu348Asp	missense	Exon 5 of 5	ENSP00000262430.4	O95822-1
	MLYCD	ENST00000851351.1		c.1071G>T	p.Glu357Asp	missense	Exon 5 of 5	ENSP00000521410.1
	MLYCD	ENST00000851350.1		c.894G>T	p.Glu298Asp	missense	Exon 4 of 4	ENSP00000521409.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 296 AN: 249582 AF XY: 0.00112

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00153 AC: 2234 AN: 1461892 Hom.: 5 Cov.: 30 AF XY: 0.00143 AC XY: 1042 AN XY: 727246

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00187 AC: 2081 AN: 1112012

Other (OTH) AF: 0.00108 AC: 65 AN: 60394

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000993 AC XY: 74 AN XY: 74510

African (AFR) AF: 0.000361 AC: 15 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000780 AC: 3

ESP6500EA AF: 0.00169 AC: 14

ExAC AF: 0.00161 AC: 194

EpiCase AF: 0.00125

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of malonyl-CoA decarboxylase (4)
-	1	1	not provided (2)
-	-	1	MLYCD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.074
DANN	Benign	0.59
DEOGEN2	Benign	0.066	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.61	N
PhyloP100		-1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.21
Sift	Benign	0.39	T
Sift4G	Benign	0.37	T
Polyphen		0.0020	B
Vest4		0.098
MutPred		0.55		Loss of helix (P = 0.1299)
MVP		0.69
MPC		0.018
ClinPred		0.0034	T
GERP RS		-6.6
Varity_R		0.095
gMVP		0.27
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs138675420; hg19: chr16-83948656; COSMIC: COSV99299332;