chr3-183015348-C-T

Variant names:

• chr3-183015348-C-T
• rs894828851
• NM_020166.5:c.*90G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_020166.5(MCCC1):​c.*90G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000779 in 1,424,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: MCCC1 NM_020166.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.971
• Publications: 0 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000849 (108/1272450) while in subpopulation EAS AF = 0.00276 (107/38804). AF 95% confidence interval is 0.00233. There are 0 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*90G>A		3_prime_UTR	Exon 19 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.*90G>A		3_prime_UTR	Exon 18 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.*90G>A		3_prime_UTR	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.*90G>A		3_prime_UTR	Exon 19 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.*90G>A		3_prime_UTR	Exon 18 of 18	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.*1865G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

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 AF: 0.0000849 AC: 108 AN: 1272450 Hom.: 0 Cov.: 19 AF XY: 0.0000809 AC XY: 52 AN XY: 643006

African (AFR) AF: 0.00 AC: 0 AN: 29662

American (AMR) AF: 0.00 AC: 0 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24946

East Asian (EAS) AF: 0.00276 AC: 107 AN: 38804

South Asian (SAS) AF: 0.00 AC: 0 AN: 81838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4952

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 941314

Other (OTH) AF: 0.00 AC: 0 AN: 54220

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-methylcrotonyl-CoA carboxylase 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.27
PhyloP100		-0.97
Mutation Taster		=100/0	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: rs894828851; hg19: chr3-182733136;