rs7622479

Positions:

• chr3-183072461-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020166.5(MCCC1):​c.396C>T​(p.Leu132=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,613,714 control chromosomes in the GnomAD database, including 694,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61476 hom., cov: 31)
  • Exomes 𝑓: 0.93 (633316 hom.)
• Consequence: MCCC1 NM_020166.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.892

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-183072461-G-A is Benign according to our data. Variant chr3-183072461-G-A is described in ClinVar as [Benign]. Clinvar id is 95943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-183072461-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.396C>T	p.Leu132=	synonymous_variant	5/19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.396C>T	p.Leu132=	synonymous_variant	5/19	1	NM_020166.5	ENSP00000265594	P1

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136280 AN: 152064 Hom.: 61446 Cov.: 31

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.933

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.907

GnomAD3 exomes AF: 0.932 AC: 233988 AN: 251030 Hom.: 109354 AF XY: 0.933 AC XY: 126775 AN XY: 135810

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.946

Gnomad FIN exome AF: 0.937

Gnomad NFE exome AF: 0.932

Gnomad OTH exome AF: 0.930

GnomAD4 exome AF: 0.930 AC: 1359764 AN: 1461532 Hom.: 633316 Cov.: 47 AF XY: 0.931 AC XY: 676829 AN XY: 727094

Gnomad4 AFR exome AF: 0.778

Gnomad4 AMR exome AF: 0.952

Gnomad4 ASJ exome AF: 0.898

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.943

Gnomad4 FIN exome AF: 0.936

Gnomad4 NFE exome AF: 0.932

Gnomad4 OTH exome AF: 0.922

GnomAD4 genome AF: 0.896 AC: 136363 AN: 152182 Hom.: 61476 Cov.: 31 AF XY: 0.899 AC XY: 66850 AN XY: 74390

Gnomad4 AFR AF: 0.794

Gnomad4 AMR AF: 0.935

Gnomad4 ASJ AF: 0.898

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.949

Gnomad4 FIN AF: 0.933

Gnomad4 NFE AF: 0.932

Gnomad4 OTH AF: 0.907

Alfa AF: 0.916 Hom.: 37329

Bravo AF: 0.894

Asia WGS AF: 0.967 AC: 3360 AN: 3476

EpiCase AF: 0.930

EpiControl AF: 0.932

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.2
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7622479; hg19: chr3-182790249;