16-83915243-C-T

Variant names:

• chr16-83915243-C-T
• rs370278897
• NM_012213.3:c.1236C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012213.3(MLYCD):​c.1236C>T​(p.Arg412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,612,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R412R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (3 hom.)
• Consequence: MLYCD NM_012213.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.84
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-83915243-C-T is Benign according to our data. Variant chr16-83915243-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460443.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000759 (1108/1460548) while in subpopulation SAS AF = 0.00355 (306/86234). AF 95% confidence interval is 0.00322. There are 3 homozygotes in GnomAdExome4. There are 624 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1236C>T	p.Arg412Arg	synonymous	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.1236C>T	p.Arg412Arg	synonymous	Exon 5 of 5	ENSP00000262430.4	O95822-1
	MLYCD	ENST00000851351.1		c.1263C>T	p.Arg421Arg	synonymous	Exon 5 of 5	ENSP00000521410.1
	MLYCD	ENST00000851350.1		c.1086C>T	p.Arg362Arg	synonymous	Exon 4 of 4	ENSP00000521409.1

Frequencies

GnomAD3 genomes AF: 0.000617 AC: 94 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000908 AC: 226 AN: 248964 AF XY: 0.00104

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000930

Gnomad NFE exome AF: 0.000718

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000759 AC: 1108 AN: 1460548 Hom.: 3 Cov.: 30 AF XY: 0.000859 AC XY: 624 AN XY: 726322

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.000112 AC: 5 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00355 AC: 306 AN: 86234

European-Finnish (FIN) AF: 0.000975 AC: 52 AN: 53324

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.000573 AC: 637 AN: 1110998

Other (OTH) AF: 0.000795 AC: 48 AN: 60342

GnomAD4 genome AF: 0.000623 AC: 95 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000738 AC XY: 55 AN XY: 74520

African (AFR) AF: 0.000144 AC: 6 AN: 41594

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68036

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

Alfa AF: 0.000621 Hom.: 0

Bravo AF: 0.000374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Deficiency of malonyl-CoA decarboxylase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.4
DANN	Benign	0.89
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

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: rs370278897; hg19: chr16-83948848;