NM_020166.5:c.137G>T

Variant names:

• chr3-183092545-C-A
• NM_020166.5:c.137G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020166.5(MCCC1):​c.137G>T​(p.Gly46Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCCC1 NM_020166.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.137G>T	p.Gly46Val	missense_variant, splice_region_variant	Exon 3 of 19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.137G>T	p.Gly46Val	missense_variant, splice_region_variant	Exon 3 of 19	1	NM_020166.5	ENSP00000265594.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.30	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.15	T;.
Sift4G	Benign	0.33	T;T
Polyphen		0.017	B;.
Vest4		0.49
MutPred		0.48		Loss of catalytic residue at T45 (P = 0.154);.;
MVP		0.95
MPC		0.17
ClinPred		0.25	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.77		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-182810333;