rs115175255

Variant names:

• chr2-71110073-C-A
• rs115175255
• NM_032601.4:c.428G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-71110073-C-A
• chr2-71110073-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032601.4(MCEE):​c.428G>T​(p.Arg143Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCEE NM_032601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14
• Publications: 13 publications found

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]

MCEE Gene-Disease associations (from GenCC):

• methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032601.4. 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
	MCEE	NM_032601.4	MANE Select	c.428G>T	p.Arg143Leu	missense	Exon 3 of 3	NP_115990.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCEE	ENST00000244217.6	TSL:1 MANE Select	c.428G>T	p.Arg143Leu	missense	Exon 3 of 3	ENSP00000244217.5
	MCEE	ENST00000413592.5	TSL:2	c.134G>T	p.Arg45Leu	missense	Exon 2 of 2	ENSP00000391140.1
	MCEE	ENST00000916433.1		c.86G>T	p.Arg29Leu	missense	Exon 2 of 2	ENSP00000586492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251110 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460974 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44706

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111322

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 113

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.1
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.69		Loss of MoRF binding (P = 6e-04)
MVP		0.87
MPC		0.56
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.93
Mutation Taster		=58/42	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: rs115175255; hg19: chr2-71337203; COSMIC: COSV54907298;