rs6748672

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104H) has been classified as Uncertain significance.

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

Publications

27 publications found

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 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

MCEE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MCEE	NM_032601.4 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 2 of 3	ENST00000244217.6	NP_115990.3	Q96PE7
MCEE	XM_047446039.1 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 2 of 3		XP_047301995.1
MCEE	XM_005264613.3 link	c.216+95G>T		intron_variant	Intron 2 of 2		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCEE	ENST00000244217.6 link	c.311G>T	p.Arg104Leu	missense_variant	Exon 2 of 3	1	NM_032601.4	ENSP00000244217.5	Q96PE7
MCEE	ENST00000486135.1 link	c.26G>T	p.Arg9Leu	missense_variant	Exon 3 of 3	3		ENSP00000441569.1	F5GZ54
MCEE	ENST00000494660.6 link	c.26G>T	p.Arg9Leu	missense_variant	Exon 2 of 2	2		ENSP00000437361.1	F5GZ54
MCEE	ENST00000413592.5 link	c.84+95G>T		intron_variant	Intron 1 of 1	2		ENSP00000391140.1	H7BZS7

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

GnomAD2 exomes

AF:

0.171

AC:

43015

AN:

251120

AF XY:

0.173

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 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

African (AFR)

AF:

0.219

AC:

7330

AN:

33472

American (AMR)

AF:

0.177

AC:

7922

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

4168

AN:

26132

East Asian (EAS)

AF:

0.217

AC:

8618

AN:

39698

South Asian (SAS)

AF:

0.204

AC:

17633

AN:

86248

European-Finnish (FIN)

AF:

0.0994

AC:

5309

AN:

53402

Middle Eastern (MID)

AF:

0.186

AC:

1071

AN:

5768

European-Non Finnish (NFE)

AF:

0.170

AC:

189378

AN:

1111594

Other (OTH)

AF:

0.176

AC:

10646

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

10786

21573

32359

43146

53932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6836

13672

20508

27344

34180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.182

AC:

27690

AN:

152184

Hom.:

2680

Cov.:

AF XY:

0.178

AC XY:

13259

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.221

AC:

9158

AN:

41512

American (AMR)

AF:

0.178

AC:

2728

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

568

AN:

3472

East Asian (EAS)

AF:

0.199

AC:

1029

AN:

5180

South Asian (SAS)

AF:

0.207

AC:

996

AN:

4816

European-Finnish (FIN)

AF:

0.0917

AC:

972

AN:

10594

Middle Eastern (MID)

AF:

0.154

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.170

AC:

11589

AN:

68000

Other (OTH)

AF:

0.195

AC:

413

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1163

2326

3490

4653

5816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

310

620

930

1240

1550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.174

Hom.:

8290

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

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Aug 26, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.

PhyloP100

0.80

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

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over