3-183034058-C-T

Variant names:

• chr3-183034058-C-T
• rs34749281
• NM_020166.5:c.1614G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020166.5(MCCC1):​c.1614G>A​(p.Ser538Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,609,446 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S538S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 31)
  • Exomes 𝑓: 0.015 (204 hom.)
• Consequence: MCCC1 NM_020166.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.890
• Publications: 4 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

LOC124906309 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036754608).
• BP6: Variant 3-183034058-C-T is Benign according to our data. Variant chr3-183034058-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1800/151588) while in subpopulation NFE AF = 0.0165 (1122/67934). AF 95% confidence interval is 0.0157. There are 17 homozygotes in GnomAd4. There are 820 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.1614G>A	p.Ser538Ser	synonymous	Exon 14 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.1287G>A	p.Ser429Ser	synonymous	Exon 13 of 18	NP_001350809.1
	MCCC1	NM_001293273.2		c.1263G>A	p.Ser421Ser	synonymous	Exon 12 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.1614G>A	p.Ser538Ser	synonymous	Exon 14 of 19	ENSP00000265594.4
	MCCC1	ENST00000492597.5	TSL:1	c.1287G>A	p.Ser429Ser	synonymous	Exon 13 of 18	ENSP00000419898.1
	MCCC1	ENST00000497830.5	TSL:1	n.*1211G>A		non_coding_transcript_exon	Exon 12 of 17	ENSP00000420088.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 151470 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00573

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00669

Gnomad FIN AF: 0.00746

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0135

GnomAD2 exomes AF: 0.0120 AC: 3016 AN: 250940 AF XY: 0.0121

Gnomad AFR exome AF: 0.00562

Gnomad AMR exome AF: 0.00801

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00879

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0146

GnomAD4 exome AF: 0.0150 AC: 21832 AN: 1457858 Hom.: 204 Cov.: 29 AF XY: 0.0147 AC XY: 10692 AN XY: 725572

African (AFR) AF: 0.00527 AC: 176 AN: 33394

American (AMR) AF: 0.00850 AC: 380 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 792 AN: 26110

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39652

South Asian (SAS) AF: 0.00746 AC: 643 AN: 86160

European-Finnish (FIN) AF: 0.00915 AC: 486 AN: 53102

Middle Eastern (MID) AF: 0.0160 AC: 83 AN: 5182

European-Non Finnish (NFE) AF: 0.0165 AC: 18257 AN: 1109314

Other (OTH) AF: 0.0168 AC: 1012 AN: 60224

GnomAD4 genome AF: 0.0119 AC: 1800 AN: 151588 Hom.: 17 Cov.: 31 AF XY: 0.0111 AC XY: 820 AN XY: 74044

African (AFR) AF: 0.00571 AC: 236 AN: 41296

American (AMR) AF: 0.0117 AC: 177 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00648 AC: 31 AN: 4782

European-Finnish (FIN) AF: 0.00746 AC: 78 AN: 10460

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1122 AN: 67934

Other (OTH) AF: 0.0134 AC: 28 AN: 2096

Alfa AF: 0.0145 Hom.: 43

Bravo AF: 0.0118

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0172 AC: 148

ExAC AF: 0.0118 AC: 1426

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0177

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0037	T
PhyloP100		0.89
Sift4G	Benign	0.079	T
Vest4		0.23
GERP RS		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34749281; hg19: chr3-182751846;