chr3-183057312-G-A

Variant names:

• chr3-183057312-G-A
• rs201041864
• NM_020166.5:c.872C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM1 PP5

The NM_020166.5(MCCC1):​c.872C>T​(p.Ala291Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,598,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000656962: Experimental studies have shown that this missense change affects MCCC1 function (PMID:16010683)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A291E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: MCCC1 NM_020166.5 missense, splice_region
• Scores: Splicing: ADA: 0.001581
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 2.82
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000656962: Experimental studies have shown that this missense change affects MCCC1 function (PMID: 16010683).; SCV001795440: Expression studies found that this variant is associated with significantly reduced MCC activity compared to wild-type (Dantas MF et al., 2005); SCV002556252: The variant was examined via transfection assays using MCCC1 deficient cells, and the variant was found with 26% enzymatic activity compared to wild-type (Dantas_2005). PMID: 25356967
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_020166.5
• PP5: Variant 3-183057312-G-A is Pathogenic according to our data. Variant chr3-183057312-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476401.

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.872C>T	p.Ala291Val	missense splice_region	Exon 8 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.545C>T	p.Ala182Val	missense splice_region	Exon 7 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.521C>T	p.Ala174Val	missense splice_region	Exon 6 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.872C>T	p.Ala291Val	missense splice_region	Exon 8 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.545C>T	p.Ala182Val	missense splice_region	Exon 7 of 18	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.*469C>T		splice_region non_coding_transcript_exon	Exon 6 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 32 AN: 230448 AF XY: 0.000129

Gnomad AFR exome AF: 0.0000681

Gnomad AMR exome AF: 0.000334

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000158 AC: 229 AN: 1446376 Hom.: 0 Cov.: 30 AF XY: 0.000134 AC XY: 96 AN XY: 718098

African (AFR) AF: 0.0000301 AC: 1 AN: 33264

American (AMR) AF: 0.000323 AC: 14 AN: 43338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000180 AC: 198 AN: 1102210

Other (OTH) AF: 0.000234 AC: 14 AN: 59772

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74320

African (AFR) AF: 0.0000483 AC: 2 AN: 41424

American (AMR) AF: 0.000262 AC: 4 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

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

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.8
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.029	D
Polyphen		0.98	D
Vest4		0.77
MVP		0.97
MPC		0.59
ClinPred		0.90	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.87
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.26
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: rs201041864; hg19: chr3-182775100;