2-71110076-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032601.4(MCEE):c.425T>A(p.Ile142Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MCEE NM_032601.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCEE	NM_032601.4	c.425T>A	p.Ile142Asn	missense_variant	3/3	ENST00000244217.6
MCEE	XM_005264613.3	c.263T>A	p.Ile88Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCEE	ENST00000244217.6	c.425T>A	p.Ile142Asn	missense_variant	3/3	1	NM_032601.4	P1
MCEE	ENST00000413592.5	c.131T>A	p.Ile44Asn	missense_variant	2/2	2
MCEE	ENST00000462609.2	n.371T>A		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MCEE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 142 of the MCEE protein (p.Ile142Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.70		.;Gain of disorder (P = 0.0409);
MVP		0.87
MPC		0.70
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.97

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-71337206;