rs7622479

Variant names:

• chr3-183072461-G-A
• rs7622479
• NM_020166.5:c.396C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020166.5(MCCC1):​c.396C>T​(p.Leu132Leu) 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
• Publications: 23 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 -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 VariationId is 95943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.396C>T	p.Leu132Leu	synonymous_variant	Exon 5 of 19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.396C>T	p.Leu132Leu	synonymous_variant	Exon 5 of 19	1	NM_020166.5	ENSP00000265594.4

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

GnomAD2 exomes AF: 0.932 AC: 233988 AN: 251030 AF XY: 0.933

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 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

African (AFR) AF: 0.778 AC: 26029 AN: 33466

American (AMR) AF: 0.952 AC: 42547 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 23465 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39668 AN: 39678

South Asian (SAS) AF: 0.943 AC: 81302 AN: 86256

European-Finnish (FIN) AF: 0.936 AC: 49960 AN: 53394

Middle Eastern (MID) AF: 0.872 AC: 5028 AN: 5768

European-Non Finnish (NFE) AF: 0.932 AC: 1036081 AN: 1111760

Other (OTH) AF: 0.922 AC: 55684 AN: 60380

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

African (AFR) AF: 0.794 AC: 32922 AN: 41484

American (AMR) AF: 0.935 AC: 14295 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3117 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.949 AC: 4570 AN: 4814

European-Finnish (FIN) AF: 0.933 AC: 9891 AN: 10600

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63415 AN: 68030

Other (OTH) AF: 0.907 AC: 1911 AN: 2106

Alfa AF: 0.914 Hom.: 39116

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

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 16, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.2
DANN	Benign	0.95
PhyloP100		0.89
Mutation Taster		=293/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7622479; hg19: chr3-182790249; COSMIC: COSV108101728;