3-183071290-A-T

Variant names:

• chr3-183071290-A-T
• rs757362635
• NM_020166.5:c.559T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020166.5(MCCC1):​c.559T>A​(p.Ser187Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S187P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MCCC1 NM_020166.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.559T>A	p.Ser187Thr	missense	Exon 6 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.232T>A	p.Ser78Thr	missense	Exon 5 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.208T>A	p.Ser70Thr	missense	Exon 4 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.559T>A	p.Ser187Thr	missense	Exon 6 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.232T>A	p.Ser78Thr	missense	Exon 5 of 18	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.*156T>A		non_coding_transcript_exon	Exon 4 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.76	N
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.42
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.029	B
Vest4		0.34
MutPred		0.55		Loss of ubiquitination at K192 (P = 0.1037)
MVP		0.97
MPC		0.21
ClinPred		0.60	D
GERP RS		3.4
Varity_R		0.14
gMVP		0.75
Mutation Taster		=52/48	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: rs757362635; hg19: chr3-182789078;