dbSNP rs937652: MCCC1:c.-101-4935G>C (chr3-183099540-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001363880.1(MCCC1):c.-290G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,429,106 control chromosomes in the GnomAD database, including 413,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 32632 hom., cov: 34)

Exomes 𝑓: 0.77 ( 381353 hom. )

Consequence

MCCC1
NM_001363880.1 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.31

Publications

16 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-183099540-C-G is Benign according to our data. Variant chr3-183099540-C-G is described in ClinVar as Benign. ClinVar VariationId is 344318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363880.1. 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_001363880.1		c.-290G>C	5_prime_UTR	Exon 1 of 18	NP_001350809.1	E9PHF7
MCCC1	NM_020166.5	MANE Select	c.-100G>C	upstream_gene	N/A	NP_064551.3
MCCC1	NM_001293273.2		c.-192G>C	upstream_gene	N/A	NP_001280202.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MCCC1	ENST00000492597.5	TSL:1	c.-101-4935G>C	intron	N/A	ENSP00000419898.1	E9PHF7
MCCC1	ENST00000908215.1		c.-100G>C	5_prime_UTR	Exon 1 of 19	ENSP00000578274.1
MCCC1	ENST00000908214.1		c.-100G>C	5_prime_UTR	Exon 1 of 18	ENSP00000578273.1

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92915

AN:

152114

Hom.:

32651

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.818

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.723

Gnomad EAS

AF:

0.649

Gnomad SAS

AF:

0.775

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.791

Gnomad OTH

AF:

0.644

GnomAD4 exome

AF:

0.766

AC:

978651

AN:

1276874

Hom.:

381353

Cov.:

AF XY:

0.769

AC XY:

486727

AN XY:

633204

show subpopulations

African (AFR)

AF:

0.238

AC:

6866

AN:

28848

American (AMR)

AF:

0.508

AC:

17847

AN:

35134

Ashkenazi Jewish (ASJ)

AF:

0.724

AC:

17454

AN:

24116

East Asian (EAS)

AF:

0.647

AC:

22649

AN:

34994

South Asian (SAS)

AF:

0.777

AC:

59651

AN:

76724

European-Finnish (FIN)

AF:

0.787

AC:

30740

AN:

39042

Middle Eastern (MID)

AF:

0.680

AC:

3711

AN:

5460

European-Non Finnish (NFE)

AF:

0.798

AC:

780469

AN:

978512

Other (OTH)

AF:

0.727

AC:

39264

AN:

54044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

11131

22262

33393

44524

55655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17868

35736

53604

71472

89340

<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:

0.610

AC:

92898

AN:

152232

Hom.:

32632

Cov.:

AF XY:

0.611

AC XY:

45449

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.250

AC:

10395

AN:

41542

American (AMR)

AF:

0.549

AC:

8397

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.723

AC:

2510

AN:

3472

East Asian (EAS)

AF:

0.649

AC:

3358

AN:

5174

South Asian (SAS)

AF:

0.774

AC:

3737

AN:

4830

European-Finnish (FIN)

AF:

0.795

AC:

8419

AN:

10592

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.791

AC:

53797

AN:

68016

Other (OTH)

AF:

0.640

AC:

1350

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1474

2947

4421

5894

7368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<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:

0.699

Hom.:

5040

Bravo

AF:

0.575

Asia WGS

AF:

0.642

AC:

2234

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-methylcrotonyl-CoA carboxylase 1 deficiency (1)

Methylcrotonyl-CoA carboxylase deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

3.0

(source)

DANN

Benign

0.79

PhyloP100

-1.3

PromoterAI

-0.23

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over