chr6-49444720-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000255.4(MMUT):c.1595G>A(p.Arg532His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,252 control chromosomes in the GnomAD database, including 101,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. R532C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 7467 hom., cov: 31)

Exomes 𝑓: 0.35 ( 93675 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0150

Publications

61 publications found

Variant links:

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMUT Gene-Disease associations (from GenCC):

methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
vitamin B12-unresponsive methylmalonic acidemia type mut-
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
vitamin B12-unresponsive methylmalonic acidemia type mut0
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MMUT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 150 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.22855 (below the threshold of 3.09). Trascript score misZ: 1.0842 (below the threshold of 3.09). GenCC associations: The gene is linked to vitamin B12-unresponsive methylmalonic acidemia type mut-, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut0.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071864724).

BP6

Variant 6-49444720-C-T is Benign according to our data. Variant chr6-49444720-C-T is described in ClinVar as Benign. ClinVar VariationId is 92681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4 link	c.1595G>A	p.Arg532His	missense_variant	Exon 9 of 13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 link	c.1595G>A	p.Arg532His	missense_variant	Exon 9 of 13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.1595G>A	p.Arg532His	missense_variant	Exon 9 of 13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45876

AN:

151788

Hom.:

7460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.349

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.288

GnomAD2 exomes

AF:

0.316

AC:

79267

AN:

250824

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.234

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.354

AC:

516885

AN:

1460346

Hom.:

93675

Cov.:

AF XY:

0.354

AC XY:

257161

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.194

AC:

6497

AN:

33430

American (AMR)

AF:

0.188

AC:

8417

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

8619

AN:

26084

East Asian (EAS)

AF:

0.230

AC:

9116

AN:

39678

South Asian (SAS)

AF:

0.357

AC:

30768

AN:

86228

European-Finnish (FIN)

AF:

0.369

AC:

19710

AN:

53400

Middle Eastern (MID)

AF:

0.250

AC:

1438

AN:

5760

European-Non Finnish (NFE)

AF:

0.371

AC:

412201

AN:

1110738

Other (OTH)

AF:

0.333

AC:

20119

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

16141

32283

48424

64566

80707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12974

25948

38922

51896

64870

<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:

0.302

AC:

45893

AN:

151906

Hom.:

7467

Cov.:

AF XY:

0.301

AC XY:

22369

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.203

AC:

8392

AN:

41430

American (AMR)

AF:

0.230

AC:

3502

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

1208

AN:

3464

East Asian (EAS)

AF:

0.219

AC:

1128

AN:

5162

South Asian (SAS)

AF:

0.371

AC:

1786

AN:

4812

European-Finnish (FIN)

AF:

0.374

AC:

3940

AN:

10546

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.368

AC:

24978

AN:

67928

Other (OTH)

AF:

0.289

AC:

610

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1589

3177

4766

6354

7943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.344

Hom.:

32517

Bravo

AF:

0.282

TwinsUK

AF:

0.383

AC:

1421

ALSPAC

AF:

0.365

AC:

1408

ESP6500AA

AF:

0.211

AC:

929

ESP6500EA

AF:

0.366

AC:

3148

ExAC

AF:

0.322

AC:

39130

Asia WGS

AF:

0.327

AC:

1139

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.337

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 28, 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: 32% of total chromosomes in ExAC -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Benign:5

Jan 13, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 23, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MUT c.1595G>A (p.Arg532His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 39104/121218 control chromosomes (6814 homozygotes) at a frequency of 0.3225924, which is approximately 134 times the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Dec 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19744961, 23754956, 27591164) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.035

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

0.58

PhyloP100

-0.015

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.43

Sift

Benign

0.056

Sift4G

Benign

0.072

Vest4

0.12

MPC

0.13

ClinPred

0.014

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.26

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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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