Genetic Variant MCCC1:p.Val439Leu (chr3-183039088-C-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PM5PP3_Moderate

The NM_020166.5(MCCC1):c.1315G>C(p.Val439Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V439M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.84

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS1

Transcript NM_020166.5 (MCCC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_020166.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-183039088-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95940.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5 link	c.1315G>C	p.Val439Leu	missense_variant	Exon 12 of 19	ENST00000265594.9	NP_064551.3	Q96RQ3A0A0S2Z693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 link	c.1315G>C	p.Val439Leu	missense_variant	Exon 12 of 19	1	NM_020166.5	ENSP00000265594.4		Q96RQ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251428

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000449

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;D;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.3

H;.;.;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.0

D;D;.;.;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;.;.;D

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

0.88

P;P;.;.;P

Vest4

0.88

MutPred

0.76

Loss of methylation at K436 (P = 0.08);.;.;.;.;

MVP

0.87

MPC

0.31

ClinPred

1.0

GERP RS

6.0

Varity_R

0.89

gMVP

0.90

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over