3-183034058-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020166.5(MCCC1):c.1614G>A(p.Ser538Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,609,446 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S538S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 31)

Exomes 𝑓: 0.015 ( 204 hom. )

Consequence

MCCC1
NM_020166.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.890

Publications

4 publications found

Variant links:

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

MCCC1 links:

LOC124906309 (HGNC:):

LOC124906309 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036754608).

BP6

Variant 3-183034058-C-T is Benign according to our data. Variant chr3-183034058-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.89 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1800/151588) while in subpopulation NFE AF = 0.0165 (1122/67934). AF 95% confidence interval is 0.0157. There are 17 homozygotes in GnomAd4. There are 820 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5 link	c.1614G>A	p.Ser538Ser	synonymous_variant	Exon 14 of 19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 link	c.1614G>A	p.Ser538Ser	synonymous_variant	Exon 14 of 19	1	NM_020166.5	ENSP00000265594.4

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1805

AN:

151470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00573

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00669

Gnomad FIN

AF:

0.00746

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0135

GnomAD2 exomes

AF:

0.0120

AC:

3016

AN:

250940

AF XY:

0.0121

show subpopulations

Gnomad AFR exome

AF:

0.00562

Gnomad AMR exome

AF:

0.00801

Gnomad ASJ exome

AF:

0.0323

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00879

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.0146

GnomAD4 exome

AF:

0.0150

AC:

21832

AN:

1457858

Hom.:

204

Cov.:

AF XY:

0.0147

AC XY:

10692

AN XY:

725572

show subpopulations

African (AFR)

AF:

0.00527

AC:

176

AN:

33394

American (AMR)

AF:

0.00850

AC:

380

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

792

AN:

26110

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39652

South Asian (SAS)

AF:

0.00746

AC:

643

AN:

86160

European-Finnish (FIN)

AF:

0.00915

AC:

486

AN:

53102

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5182

European-Non Finnish (NFE)

AF:

0.0165

AC:

18257

AN:

1109314

Other (OTH)

AF:

0.0168

AC:

1012

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

1005

2010

3016

4021

5026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

674

1348

2022

2696

3370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0119

AC:

1800

AN:

151588

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

820

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.00571

AC:

236

AN:

41296

American (AMR)

AF:

0.0117

AC:

177

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00648

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00746

AC:

AN:

10460

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1122

AN:

67934

Other (OTH)

AF:

0.0134

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0172

AC:

148

ExAC

AF:

0.0118

AC:

1426

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 14, 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

- -

Jan 27, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

3-methylcrotonyl-CoA carboxylase 1 deficiency

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MCCC1: BP4, BP7, BS1, BS2 -

Methylcrotonyl-CoA carboxylase deficiency

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

9.3

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0037

PhyloP100

0.89

Sift4G

Benign

0.079

Vest4

0.23

GERP RS

2.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over