3-183099540-C-T

Variant names:

• chr3-183099540-C-T
• rs937652
• ENST00000492597.5:c.-101-4935G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000492597.5(MCCC1):​c.-101-4935G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,278,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: MCCC1 ENST00000492597.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 16 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.-100G>A		upstream_gene_variant		ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.-100G>A		upstream_gene_variant		1	NM_020166.5	ENSP00000265594.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1278240 Hom.: 0 Cov.: 19 AF XY: 0.00000158 AC XY: 1 AN XY: 633834

African (AFR) AF: 0.00 AC: 0 AN: 28882

American (AMR) AF: 0.0000284 AC: 1 AN: 35156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35000

South Asian (SAS) AF: 0.00 AC: 0 AN: 76764

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 979708

Other (OTH) AF: 0.00 AC: 0 AN: 54078

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.1
DANN	Benign	0.93
PhyloP100		-1.3
PromoterAI		-0.24	Neutral

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: rs937652; hg19: chr3-182817328;