ENST00000492597.5:c.-101-4935G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000492597.5(MCCC1):​c.-101-4935G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,429,106 control chromosomes in the GnomAD database, including 413,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (32632 hom., cov: 34)
  • Exomes 𝑓: 0.77 (381353 hom.)
• Consequence: MCCC1 ENST00000492597.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 3-183099540-C-G is Benign according to our data. Variant chr3-183099540-C-G is described in ClinVar as Benign. ClinVar VariationId is 344318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000492597.5. 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_001363880.1		c.-290G>C		5_prime_UTR	Exon 1 of 18	NP_001350809.1
	MCCC1	NM_020166.5	MANE Select	c.-100G>C		upstream_gene	N/A	NP_064551.3
	MCCC1	NM_001293273.2		c.-192G>C		upstream_gene	N/A	NP_001280202.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000492597.5	TSL:1	c.-101-4935G>C		intron	N/A	ENSP00000419898.1
	MCCC1	ENST00000476176.5	TSL:2	c.-100G>C		5_prime_UTR	Exon 1 of 16	ENSP00000420433.1
	MCCC1	ENST00000629669.2	TSL:5	c.-214G>C		5_prime_UTR	Exon 1 of 18	ENSP00000486824.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92915 AN: 152114 Hom.: 32651 Cov.: 34

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.791

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.766 AC: 978651 AN: 1276874 Hom.: 381353 Cov.: 19 AF XY: 0.769 AC XY: 486727 AN XY: 633204

African (AFR) AF: 0.238 AC: 6866 AN: 28848

American (AMR) AF: 0.508 AC: 17847 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 17454 AN: 24116

East Asian (EAS) AF: 0.647 AC: 22649 AN: 34994

South Asian (SAS) AF: 0.777 AC: 59651 AN: 76724

European-Finnish (FIN) AF: 0.787 AC: 30740 AN: 39042

Middle Eastern (MID) AF: 0.680 AC: 3711 AN: 5460

European-Non Finnish (NFE) AF: 0.798 AC: 780469 AN: 978512

Other (OTH) AF: 0.727 AC: 39264 AN: 54044

GnomAD4 genome AF: 0.610 AC: 92898 AN: 152232 Hom.: 32632 Cov.: 34 AF XY: 0.611 AC XY: 45449 AN XY: 74428

African (AFR) AF: 0.250 AC: 10395 AN: 41542

American (AMR) AF: 0.549 AC: 8397 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2510 AN: 3472

East Asian (EAS) AF: 0.649 AC: 3358 AN: 5174

South Asian (SAS) AF: 0.774 AC: 3737 AN: 4830

European-Finnish (FIN) AF: 0.795 AC: 8419 AN: 10592

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.791 AC: 53797 AN: 68016

Other (OTH) AF: 0.640 AC: 1350 AN: 2110

Alfa AF: 0.699 Hom.: 5040

Bravo AF: 0.575

Asia WGS AF: 0.642 AC: 2234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcrotonyl-CoA carboxylase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

3-methylcrotonyl-CoA carboxylase 1 deficiency Benign:1

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.0
DANN	Benign	0.79
PhyloP100		-1.3
PromoterAI		-0.23	Neutral
Mutation Taster		=299/1	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: rs937652; hg19: chr3-182817328; COSMIC: COSV55606960; COSMIC: COSV55606960;