rs776473131

Variant names:

• chr2-71110081-CT-C
• rs776473131
• NM_032601.4:c.419delA

Your query was ambiguous. Multiple possible variants found:

• chr2-71110081-CT-C
• chr2-71110081-CT-CTT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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]

ACMG classification

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
MCEE	NM_032601.4	c.419delA	p.Lys140ArgfsTer6	frameshift_variant	Exon 3 of 3	ENST00000244217.6	NP_115990.3
MCEE	XM_005264613.3	c.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
MCEE	ENST00000244217.6	c.419delA	p.Lys140ArgfsTer6	frameshift_variant	Exon 3 of 3	1	NM_032601.4	ENSP00000244217.5
MCEE	ENST00000413592.5	c.125delA	p.Lys42ArgfsTer6	frameshift_variant	Exon 2 of 2	2		ENSP00000391140.1
MCEE	ENST00000462609.2	n.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

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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

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

Other links and lift over

dbSNP: rs776473131; hg19: chr2-71337211;