6-49447735-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.1495G>A(p.Ala499Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,609,812 control chromosomes in the GnomAD database, including 9,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A499P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 818 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8316 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.422

Publications

25 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=0.001824379).

BP6

Variant 6-49447735-C-T is Benign according to our data. Variant chr6-49447735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4 link	c.1495G>A	p.Ala499Thr	missense_variant	Exon 8 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4 link	c.1495G>A	p.Ala499Thr	missense_variant	Exon 8 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.1495G>A	p.Ala499Thr	missense_variant	Exon 8 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15706

AN:

151522

Hom.:

817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0991

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.0810

Gnomad ASJ

AF:

0.0912

Gnomad EAS

AF:

0.0683

Gnomad SAS

AF:

0.0903

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.0979

AC:

24502

AN:

250150

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.0980

Gnomad AMR exome

AF:

0.0576

Gnomad ASJ exome

AF:

0.0809

Gnomad EAS exome

AF:

0.0621

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0969

GnomAD4 exome

AF:

0.105

AC:

152988

AN:

1458188

Hom.:

8316

Cov.:

AF XY:

0.105

AC XY:

76279

AN XY:

725478

show subpopulations

African (AFR)

AF:

0.0955

AC:

3187

AN:

33374

American (AMR)

AF:

0.0595

AC:

2661

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0820

AC:

2137

AN:

26070

East Asian (EAS)

AF:

0.0813

AC:

3216

AN:

39534

South Asian (SAS)

AF:

0.0982

AC:

8464

AN:

86164

European-Finnish (FIN)

AF:

0.134

AC:

7151

AN:

53338

Middle Eastern (MID)

AF:

0.128

AC:

737

AN:

5750

European-Non Finnish (NFE)

AF:

0.108

AC:

119299

AN:

1109038

Other (OTH)

AF:

0.102

AC:

6136

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

6634

13268

19901

26535

33169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4260

8520

12780

17040

21300

<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:

0.104

AC:

15719

AN:

151624

Hom.:

818

Cov.:

AF XY:

0.105

AC XY:

7748

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.0992

AC:

4107

AN:

41390

American (AMR)

AF:

0.0808

AC:

1232

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.0912

AC:

316

AN:

3464

East Asian (EAS)

AF:

0.0685

AC:

353

AN:

5154

South Asian (SAS)

AF:

0.0900

AC:

433

AN:

4810

European-Finnish (FIN)

AF:

0.141

AC:

1487

AN:

10524

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7383

AN:

67734

Other (OTH)

AF:

0.105

AC:

220

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

713

1426

2139

2852

3565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.104

Hom.:

2766

Bravo

AF:

0.0997

TwinsUK

AF:

0.105

AC:

388

ALSPAC

AF:

0.114

AC:

439

ESP6500AA

AF:

0.0988

AC:

435

ESP6500EA

AF:

0.106

AC:

908

ExAC

AF:

0.0988

AC:

11990

Asia WGS

AF:

0.0640

AC:

220

AN:

3476

EpiCase

AF:

0.111

EpiControl

AF:

0.113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Benign:3Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 28, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MUT c.1495G>A (p.Ala499Thr) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.099 in 275710 control chromosomes in the gnomAD database, including 1409 homozygotes. The observed variant frequency is approximately 41-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MUT causing Methylmalonic Acidemia phenotype (0.0024), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

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

0.059

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.35

CADD

Benign

6.9

(source)

DANN

Benign

0.95

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0018

MetaSVM

Uncertain

-0.25

PhyloP100

0.42

PrimateAI

Benign

0.31

PROVEAN

Benign

0.34

REVEL

Benign

0.19

Sift

Benign

0.085

Sift4G

Benign

0.17

Vest4

0.047

MPC

0.088

ClinPred

0.0046

GERP RS

-2.1

gMVP

0.27

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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