rs11540930

Variant names:

• chr3-183099464-T-C
• rs11540930
• NM_020166.5:c.-24A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-183099464-T-C
• chr3-183099464-T-A
• chr3-183099464-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020166.5(MCCC1):​c.-24A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,592,920 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: MCCC1 NM_020166.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.97
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-183099464-T-C is Benign according to our data. Variant chr3-183099464-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00708 (1078/152300) while in subpopulation AFR AF = 0.0246 (1022/41562). AF 95% confidence interval is 0.0233. There are 16 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.-24A>G		5_prime_UTR	Exon 1 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.-214A>G		5_prime_UTR	Exon 1 of 18	NP_001350809.1	E9PHF7
	MCCC1	NM_001293273.2		c.-116A>G		5_prime_UTR	Exon 1 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.-24A>G		5_prime_UTR	Exon 1 of 19	ENSP00000265594.4	Q96RQ3
	MCCC1	ENST00000492597.5	TSL:1	c.-101-4859A>G		intron	N/A	ENSP00000419898.1	E9PHF7
	MCCC1	ENST00000497830.5	TSL:1	n.-24A>G		non_coding_transcript_exon	Exon 1 of 17	ENSP00000420088.1	F2Z3E2

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1054 AN: 152182 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00158 AC: 322 AN: 204336 AF XY: 0.00105

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000567

Gnomad OTH exome AF: 0.000962

GnomAD4 exome AF: 0.000732 AC: 1054 AN: 1440620 Hom.: 9 Cov.: 30 AF XY: 0.000608 AC XY: 435 AN XY: 715142

African (AFR) AF: 0.0247 AC: 811 AN: 32796

American (AMR) AF: 0.00182 AC: 77 AN: 42244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 38404

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50242

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5748

European-Non Finnish (NFE) AF: 0.0000227 AC: 25 AN: 1102614

Other (OTH) AF: 0.00205 AC: 122 AN: 59512

GnomAD4 genome AF: 0.00708 AC: 1078 AN: 152300 Hom.: 16 Cov.: 33 AF XY: 0.00669 AC XY: 498 AN XY: 74476

African (AFR) AF: 0.0246 AC: 1022 AN: 41562

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.00796

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.52
PhyloP100		-3.0
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11540930; hg19: chr3-182817252;