rs35706839

Variant names:

• chr3-183015467-C-T
• rs35706839
• NM_020166.5:c.2149G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020166.5(MCCC1):​c.2149G>A​(p.Glu717Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000843 in 1,614,144 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: MCCC1 NM_020166.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.95
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005342722).
• BP6: Variant 3-183015467-C-T is Benign according to our data. Variant chr3-183015467-C-T is described in ClinVar as Benign. ClinVar VariationId is 138181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00454 (692/152292) while in subpopulation AFR AF = 0.0159 (661/41558). AF 95% confidence interval is 0.0149. There are 3 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.2149G>A	p.Glu717Lys	missense	Exon 19 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.1822G>A	p.Glu608Lys	missense	Exon 18 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.1798G>A	p.Glu600Lys	missense	Exon 17 of 17	NP_001280202.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.2149G>A	p.Glu717Lys	missense	Exon 19 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.1822G>A	p.Glu608Lys	missense	Exon 18 of 18	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.*1746G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00113 AC: 282 AN: 250644 AF XY: 0.000767

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000457 AC: 668 AN: 1461852 Hom.: 4 Cov.: 31 AF XY: 0.000381 AC XY: 277 AN XY: 727238

African (AFR) AF: 0.0159 AC: 533 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111984

Other (OTH) AF: 0.000977 AC: 59 AN: 60394

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00444 AC XY: 331 AN XY: 74472

African (AFR) AF: 0.0159 AC: 661 AN: 41558

American (AMR) AF: 0.00124 AC: 19 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00177 Hom.: 5

Bravo AF: 0.00520

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0053	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.52
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.88	P
Vest4		0.54
MVP		0.99
MPC		0.15
ClinPred		0.024	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.82
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs35706839; hg19: chr3-182733255;