rs6748672

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032601.4(MCEE):c.311G>T(p.Arg104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,613,596 control chromosomes in the GnomAD database, including 25,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2680 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22488 hom. )

Consequence

MCEE
NM_032601.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.801

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]

MCEE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028464198).

BP6

Variant 2-71124273-C-A is Benign according to our data. Variant chr2-71124273-C-A is described in ClinVar as [Benign]. Clinvar id is 138183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MCEE	NM_032601.4 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant	2/3	ENST00000244217.6	NP_115990.3
MCEE	XM_047446039.1 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant	2/3		XP_047301995.1
MCEE	XM_005264613.3 linkuse as main transcript	c.216+95G>T		intron_variant			XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MCEE	ENST00000244217.6 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant	2/3	1	NM_032601.4	ENSP00000244217	P1
MCEE	ENST00000486135.1 linkuse as main transcript	c.26G>T	p.Arg9Leu	missense_variant	3/3	3		ENSP00000441569
MCEE	ENST00000494660.6 linkuse as main transcript	c.26G>T	p.Arg9Leu	missense_variant	2/2	2		ENSP00000437361
MCEE	ENST00000413592.5 linkuse as main transcript	c.84+95G>T		intron_variant		2		ENSP00000391140

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27671

AN:

152066

Hom.:

2675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.0917

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.171

AC:

43015

AN:

251120

Hom.:

3898

AF XY:

0.173

AC XY:

23463

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.179

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.0954

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.172

AC:

252075

AN:

1461412

Hom.:

22488

Cov.:

AF XY:

0.173

AC XY:

125908

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.219

Gnomad4 AMR exome

AF:

0.177

Gnomad4 ASJ exome

AF:

0.159

Gnomad4 EAS exome

AF:

0.217

Gnomad4 SAS exome

AF:

0.204

Gnomad4 FIN exome

AF:

0.0994

Gnomad4 NFE exome

AF:

0.170

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.182

AC:

27690

AN:

152184

Hom.:

2680

Cov.:

AF XY:

0.178

AC XY:

13259

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.221

Gnomad4 AMR

AF:

0.178

Gnomad4 ASJ

AF:

0.164

Gnomad4 EAS

AF:

0.199

Gnomad4 SAS

AF:

0.207

Gnomad4 FIN

AF:

0.0917

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.195

Alfa

AF:

0.168

Hom.:

3537

Bravo

AF:

0.188

TwinsUK

AF:

0.170

AC:

632

ALSPAC

AF:

0.177

AC:

681

ESP6500AA

AF:

0.228

AC:

1003

ESP6500EA

AF:

0.168

AC:

1449

ExAC

AF:

0.174

AC:

21100

EpiCase

AF:

0.174

EpiControl

AF:

0.177

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 17% of total chromosomes in ExAC -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.9

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.97

D;.;D

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

N;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.5

D;N;N

REVEL

Benign

0.088

Sift

Uncertain

0.024

D;D;D

Sift4G

Uncertain

0.035

D;D;D

Polyphen

0.010

B;.;.

Vest4

0.038

MPC

0.13

ClinPred

0.0053

GERP RS

-4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over