rs7622479

Variant names:

• chr3-183072461-G-A
• rs7622479
• NM_020166.5:c.396C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020166.5(MCCC1):​c.396C>T​(p.Leu132Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,613,714 control chromosomes in the GnomAD database, including 694,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61476 hom., cov: 31)
  • Exomes 𝑓: 0.93 (633316 hom.)
• Consequence: MCCC1 NM_020166.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.892
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-183072461-G-A is Benign according to our data. Variant chr3-183072461-G-A is described in ClinVar as Benign. ClinVar VariationId is 95943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	NM_020166.5	MANE Select	c.396C>T	p.Leu132Leu	synonymous	Exon 5 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.69C>T	p.Leu23Leu	synonymous	Exon 4 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.141-1104C>T		intron	N/A	NP_001280202.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.396C>T	p.Leu132Leu	synonymous	Exon 5 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.69C>T	p.Leu23Leu	synonymous	Exon 4 of 18	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.*89-1104C>T		intron	N/A	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136280 AN: 152064 Hom.: 61446 Cov.: 31

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.933

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.907

GnomAD2 exomes AF: 0.932 AC: 233988 AN: 251030 AF XY: 0.933

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.937

Gnomad NFE exome AF: 0.932

Gnomad OTH exome AF: 0.930

GnomAD4 exome AF: 0.930 AC: 1359764 AN: 1461532 Hom.: 633316 Cov.: 47 AF XY: 0.931 AC XY: 676829 AN XY: 727094

African (AFR) AF: 0.778 AC: 26029 AN: 33466

American (AMR) AF: 0.952 AC: 42547 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 23465 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39668 AN: 39678

South Asian (SAS) AF: 0.943 AC: 81302 AN: 86256

European-Finnish (FIN) AF: 0.936 AC: 49960 AN: 53394

Middle Eastern (MID) AF: 0.872 AC: 5028 AN: 5768

European-Non Finnish (NFE) AF: 0.932 AC: 1036081 AN: 1111760

Other (OTH) AF: 0.922 AC: 55684 AN: 60380

GnomAD4 genome AF: 0.896 AC: 136363 AN: 152182 Hom.: 61476 Cov.: 31 AF XY: 0.899 AC XY: 66850 AN XY: 74390

African (AFR) AF: 0.794 AC: 32922 AN: 41484

American (AMR) AF: 0.935 AC: 14295 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3117 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.949 AC: 4570 AN: 4814

European-Finnish (FIN) AF: 0.933 AC: 9891 AN: 10600

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63415 AN: 68030

Other (OTH) AF: 0.907 AC: 1911 AN: 2106

Alfa AF: 0.914 Hom.: 39116

Bravo AF: 0.894

Asia WGS AF: 0.967 AC: 3360 AN: 3476

EpiCase AF: 0.930

EpiControl AF: 0.932

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	3-methylcrotonyl-CoA carboxylase 1 deficiency (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.2
DANN	Benign	0.95
PhyloP100		0.89
Mutation Taster		=293/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7622479; hg19: chr3-182790249; COSMIC: COSV108101728;