3-183034058-C-T

Position:

chr3-183034058-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000265594.9(MCCC1):c.1614G>A(p.Ser538=) 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
ENST00000265594.9 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.890

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC1	NM_020166.5 linkuse as main transcript	c.1614G>A	p.Ser538=	synonymous_variant	14/19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 linkuse as main transcript	c.1614G>A	p.Ser538=	synonymous_variant	14/19	1	NM_020166.5	ENSP00000265594	P1

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

GnomAD3 exomes

AF:

0.0120

AC:

3016

AN:

250940

Hom.:

AF XY:

0.0121

AC XY:

1643

AN XY:

135720

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 SAS exome

AF:

0.00771

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

Gnomad4 AFR exome

AF:

0.00527

Gnomad4 AMR exome

AF:

0.00850

Gnomad4 ASJ exome

AF:

0.0303

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00746

Gnomad4 FIN exome

AF:

0.00915

Gnomad4 NFE exome

AF:

0.0165

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0119

AC:

1800

AN:

151588

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

820

AN XY:

74044

show subpopulations

Gnomad4 AFR

AF:

0.00571

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00648

Gnomad4 FIN

AF:

0.00746

Gnomad4 NFE

AF:

0.0165

Gnomad4 OTH

AF:

0.0134

Alfa

AF:

0.0142

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

3-methylcrotonyl-CoA carboxylase 1 deficiency

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MCCC1: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Methylcrotonyl-CoA carboxylase deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

9.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0037

MutationTaster

Benign

1.0

D;D;D

Sift4G

Benign

0.079

Vest4

0.23

GERP RS

2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over