rs776473131

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_032601.4(MCEE):​c.419delA​(p.Lys140ArgfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000267 in 1,612,086 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 31)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

MCEE
NM_032601.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23
Variant links:
Genes affected
MCEE (HGNC:16732): (methylmalonyl-CoA epimerase) The product of this gene catalyzes the interconversion of D- and L-methylmalonyl-CoA during the degradation of branched chain amino acids. odd chain-length fatty acids, and other metabolites. Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MCEENM_032601.4 linkc.419delA p.Lys140ArgfsTer6 frameshift_variant Exon 3 of 3 ENST00000244217.6 NP_115990.3 Q96PE7
MCEEXM_005264613.3 linkc.257delA p.Lys86ArgfsTer6 frameshift_variant Exon 3 of 3 XP_005264670.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MCEEENST00000244217.6 linkc.419delA p.Lys140ArgfsTer6 frameshift_variant Exon 3 of 3 1 NM_032601.4 ENSP00000244217.5 Q96PE7
MCEEENST00000413592.5 linkc.125delA p.Lys42ArgfsTer6 frameshift_variant Exon 2 of 2 2 ENSP00000391140.1 H7BZS7
MCEEENST00000462609.2 linkn.365delA non_coding_transcript_exon_variant Exon 5 of 5 3

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151896
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
9
AN:
250236
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000708
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1460190
Hom.:
0
Cov.:
30
AF XY:
0.0000248
AC XY:
18
AN XY:
726446
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151896
Hom.:
1
Cov.:
31
AF XY:
0.0000539
AC XY:
4
AN XY:
74190
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 14, 2024Variant summary: MCEE c.419delA (p.Lys140ArgfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 3.6e-05 in 250236 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.419delA has been reported in the literature in at least one individual affected with Parkinson disease, dementia, stroke and elevated levels of methylmalonic acid (e.g., Andrasson_2019). While the current variant may not result in NMD, it alters several amino acids located in the Vicinal oxygen chelate (VOC) domain. It is unclear what impact the variant will have on the function of this protein. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31146325). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776473131; hg19: chr2-71337211; API