ENST00000497830.5:n.*1820A>T

Variant names:

• chr3-183015393-T-A
• rs186406584
• ENST00000497830.5:n.*1820A>T

Variant summary

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

The ENST00000497830.5(MCCC1):​n.*1820A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: MCCC1 ENST00000497830.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-methylcrotonyl-CoA carboxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000768 (117/152274) while in subpopulation NFE AF = 0.00126 (86/68016). AF 95% confidence interval is 0.00105. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.*45A>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.*45A>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_020166.5	ENSP00000265594.4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00102 AC: 256 AN: 251364 AF XY: 0.00105

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00114 AC: 1668 AN: 1459542 Hom.: 0 Cov.: 30 AF XY: 0.00114 AC XY: 826 AN XY: 726252

African (AFR) AF: 0.000209 AC: 7 AN: 33448

American (AMR) AF: 0.00105 AC: 47 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86168

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53362

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5742

European-Non Finnish (NFE) AF: 0.00133 AC: 1475 AN: 1109992

Other (OTH) AF: 0.00114 AC: 69 AN: 60310

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74466

African (AFR) AF: 0.000361 AC: 15 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000717 Hom.: 0

Bravo AF: 0.000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.84
DANN	Benign	0.74
PhyloP100		-0.071
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: rs186406584; hg19: chr3-182733181;