3-183042285-T-G

Variant names:

• chr3-183042285-T-G
• rs10513789
• NM_020166.5:c.1084-535A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000265594.9(MCCC1):​c.1084-535A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,204 control chromosomes in the GnomAD database, including 4,476 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4476 hom., cov: 33)
• Consequence: MCCC1 ENST00000265594.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.708
• Publications: 40 publications found

Genes affected

MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. [provided by RefSeq, Jul 2008]

MCCC1 Gene-Disease associations (from GenCC):

• 3-methylcrotonyl-CoA carboxylase 1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-methylcrotonyl-CoA carboxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265594.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	NM_020166.5	MANE Select	c.1084-535A>C		intron	N/A	NP_064551.3
	MCCC1	NM_001363880.1		c.757-535A>C		intron	N/A	NP_001350809.1
	MCCC1	NM_001293273.2		c.733-535A>C		intron	N/A	NP_001280202.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.1084-535A>C		intron	N/A	ENSP00000265594.4
	MCCC1	ENST00000492597.5	TSL:1	c.757-535A>C		intron	N/A	ENSP00000419898.1
	MCCC1	ENST00000497830.5	TSL:1	n.*681-535A>C		intron	N/A	ENSP00000420088.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34250 AN: 152086 Hom.: 4461 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.210

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.225 AC: 34288 AN: 152204 Hom.: 4476 Cov.: 33 AF XY: 0.231 AC XY: 17211 AN XY: 74410

African (AFR) AF: 0.194 AC: 8055 AN: 41538

American (AMR) AF: 0.319 AC: 4879 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3470

East Asian (EAS) AF: 0.582 AC: 3009 AN: 5172

South Asian (SAS) AF: 0.307 AC: 1481 AN: 4826

European-Finnish (FIN) AF: 0.199 AC: 2104 AN: 10592

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13291 AN: 67992

Other (OTH) AF: 0.217 AC: 459 AN: 2114

Alfa AF: 0.215 Hom.: 13537

Bravo AF: 0.234

Asia WGS AF: 0.412 AC: 1430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.69
DANN	Benign	0.48
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs10513789; hg19: chr3-182760073;