3-183020165-C-T

Position:

chr3-183020165-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_020166.5(MCCC1):c.1942G>A(p.Gly648Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 2.64

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:

MCCC1 (HGNC:):

MCCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040912896).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000552 (84/152146) while in subpopulation NFE AF= 0.000911 (62/68024). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC1	NM_020166.5 linkuse as main transcript	c.1942G>A	p.Gly648Ser	missense_variant	17/19	ENST00000265594.9	NP_064551.3	Q96RQ3A0A0S2Z693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 linkuse as main transcript	c.1942G>A	p.Gly648Ser	missense_variant	17/19	1	NM_020166.5	ENSP00000265594.4		Q96RQ3

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000485

AC:

122

AN:

251326

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000889

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00101

AC:

1472

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

657

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000552

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000849

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 29, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.1942G>A (p.G648S) alteration is located in exon 17 (coding exon 17) of the MCCC1 gene. This alteration results from a G to A substitution at nucleotide position 1942, causing the glycine (G) at amino acid position 648 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Methylcrotonyl-CoA carboxylase deficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 23, 2020

- -

MCCC1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The MCCC1 c.1942G>A variant is predicted to result in the amino acid substitution p.Gly648Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 21796119) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.32

T;T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.36

N;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

N;N;.

REVEL

Benign

0.17

Sift

Benign

0.30

T;T;.

Sift4G

Benign

0.37

T;T;T

Polyphen

0.022

B;P;.

Vest4

0.20

MVP

0.88

MPC

0.18

ClinPred

0.032

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.059

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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