Genetic Variant MCCC1:c.*45A>T (chr3-183015393-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_020166.5(MCCC1):c.*45A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0710

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: Orphanet, ClinGen

MCCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000768 (117/152274) while in subpopulation NFE AF = 0.00126 (86/68016). AF 95% confidence interval is 0.00105. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	Effect	Exon Rank	Protein	UniProt
MCCC1	NM_020166.5	MANE Select	c.*45A>T	3_prime_UTR	Exon 19 of 19	NP_064551.3
MCCC1	NM_001363880.1		c.*45A>T	3_prime_UTR	Exon 18 of 18	NP_001350809.1	E9PHF7
MCCC1	NM_001293273.2		c.*45A>T	3_prime_UTR	Exon 17 of 17	NP_001280202.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.*45A>T	3_prime_UTR	Exon 19 of 19	ENSP00000265594.4	Q96RQ3
MCCC1	ENST00000492597.5	TSL:1	c.*45A>T	3_prime_UTR	Exon 18 of 18	ENSP00000419898.1	E9PHF7
MCCC1	ENST00000497830.5	TSL:1	n.*1820A>T	non_coding_transcript_exon	Exon 17 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00102

AC:

256

AN:

251364

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00114

AC:

1668

AN:

1459542

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

826

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33448

American (AMR)

AF:

0.00105

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00133

AC:

1475

AN:

1109992

Other (OTH)

AF:

0.00114

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

150

200

250

<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:

0.000768

AC:

117

AN:

152274

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41562

American (AMR)

AF:

0.000523

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000717

Hom.:

Bravo

AF:

0.000718

ClinVar

ClinVar submissions as Germline

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.84

(source)

DANN

Benign

0.74

PhyloP100

-0.071

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over