Genetic Variant MCCC1:p.Ala291Glu (chr3-183057312-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_020166.5(MCCC1):c.872C>A(p.Ala291Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A291V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MCCC1
NM_020166.5 missense, splice_region

Scores

Splicing: ADA: 0.0006603

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
3-methylcrotonyl-CoA carboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

MCCC1 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr3-183057312-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476401.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020166.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCCC1	NM_020166.5	MANE Select	c.872C>A	p.Ala291Glu	missense splice_region	Exon 8 of 19	NP_064551.3
MCCC1	NM_001363880.1		c.545C>A	p.Ala182Glu	missense splice_region	Exon 7 of 18	NP_001350809.1	E9PHF7
MCCC1	NM_001293273.2		c.521C>A	p.Ala174Glu	missense splice_region	Exon 6 of 17	NP_001280202.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.872C>A	p.Ala291Glu	missense splice_region	Exon 8 of 19	ENSP00000265594.4	Q96RQ3
MCCC1	ENST00000492597.5	TSL:1	c.545C>A	p.Ala182Glu	missense splice_region	Exon 7 of 18	ENSP00000419898.1	E9PHF7
MCCC1	ENST00000497830.5	TSL:1	n.*469C>A		splice_region non_coding_transcript_exon	Exon 6 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-methylcrotonyl-CoA carboxylase 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

2.8

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.56

MutPred

0.86

Gain of disorder (P = 0.0461)

MVP

0.98

MPC

0.65

ClinPred

1.0

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.94

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00066

dbscSNV1_RF

Benign

0.35

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over