6-49435569-T-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000255.4(MMUT):​c.2011A>G​(p.Ile671Val) variant causes a missense change. The variant allele was found at a frequency of 0.606 in 1,613,526 control chromosomes in the GnomAD database, including 300,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 26674 hom., cov: 33)
Exomes 𝑓: 0.61 ( 273683 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

2
14

Clinical Significance

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

Conservation

PhyloP100: 3.90

Publications

44 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000255.4
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=7.249867E-5).
BP6
Variant 6-49435569-T-C is Benign according to our data. Variant chr6-49435569-T-C is described in ClinVar as [Benign]. Clinvar id is 92685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMUTNM_000255.4 linkc.2011A>G p.Ile671Val missense_variant Exon 12 of 13 ENST00000274813.4 NP_000246.2 P22033A0A024RD82B2R6K1
MMUTXM_005249143.4 linkc.2011A>G p.Ile671Val missense_variant Exon 12 of 13 XP_005249200.1 P22033A0A024RD82

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMUTENST00000274813.4 linkc.2011A>G p.Ile671Val missense_variant Exon 12 of 13 1 NM_000255.4 ENSP00000274813.3 P22033

Frequencies

GnomAD3 genomes
AF:
0.588
AC:
89383
AN:
151988
Hom.:
26651
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.592
Gnomad AMI
AF:
0.638
Gnomad AMR
AF:
0.436
Gnomad ASJ
AF:
0.564
Gnomad EAS
AF:
0.460
Gnomad SAS
AF:
0.650
Gnomad FIN
AF:
0.602
Gnomad MID
AF:
0.481
Gnomad NFE
AF:
0.625
Gnomad OTH
AF:
0.554
GnomAD2 exomes
AF:
0.562
AC:
140906
AN:
250646
AF XY:
0.573
show subpopulations
Gnomad AFR exome
AF:
0.595
Gnomad AMR exome
AF:
0.316
Gnomad ASJ exome
AF:
0.546
Gnomad EAS exome
AF:
0.468
Gnomad FIN exome
AF:
0.593
Gnomad NFE exome
AF:
0.621
Gnomad OTH exome
AF:
0.556
GnomAD4 exome
AF:
0.608
AC:
888933
AN:
1461420
Hom.:
273683
Cov.:
55
AF XY:
0.610
AC XY:
443448
AN XY:
726986
show subpopulations
African (AFR)
AF:
0.586
AC:
19622
AN:
33478
American (AMR)
AF:
0.331
AC:
14771
AN:
44656
Ashkenazi Jewish (ASJ)
AF:
0.550
AC:
14374
AN:
26136
East Asian (EAS)
AF:
0.439
AC:
17438
AN:
39688
South Asian (SAS)
AF:
0.641
AC:
55289
AN:
86232
European-Finnish (FIN)
AF:
0.599
AC:
31981
AN:
53390
Middle Eastern (MID)
AF:
0.556
AC:
3202
AN:
5754
European-Non Finnish (NFE)
AF:
0.626
AC:
696315
AN:
1111710
Other (OTH)
AF:
0.595
AC:
35941
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
20030
40061
60091
80122
100152
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
18500
37000
55500
74000
92500
<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:
0.588
AC:
89445
AN:
152106
Hom.:
26674
Cov.:
33
AF XY:
0.583
AC XY:
43327
AN XY:
74362
show subpopulations
African (AFR)
AF:
0.592
AC:
24568
AN:
41472
American (AMR)
AF:
0.435
AC:
6651
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.564
AC:
1958
AN:
3470
East Asian (EAS)
AF:
0.460
AC:
2383
AN:
5180
South Asian (SAS)
AF:
0.650
AC:
3129
AN:
4816
European-Finnish (FIN)
AF:
0.602
AC:
6382
AN:
10594
Middle Eastern (MID)
AF:
0.476
AC:
140
AN:
294
European-Non Finnish (NFE)
AF:
0.625
AC:
42485
AN:
67980
Other (OTH)
AF:
0.553
AC:
1168
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
1893
3785
5678
7570
9463
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
766
1532
2298
3064
3830
<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:
0.599
Hom.:
79528
Bravo
AF:
0.568
TwinsUK
AF:
0.636
AC:
2360
ALSPAC
AF:
0.626
AC:
2411
ESP6500AA
AF:
0.588
AC:
2590
ESP6500EA
AF:
0.617
AC:
5304
ExAC
AF:
0.574
AC:
69652
Asia WGS
AF:
0.547
AC:
1906
AN:
3478
EpiCase
AF:
0.606
EpiControl
AF:
0.600

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:6
Nov 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 19, 2021
Pars Genome Lab
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. -

Jan 03, 2017
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 05, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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: 58% of total chromosomes in ExAC -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 28, 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

- -

not provided Benign:2
Dec 04, 2018
GeneDx
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

- -

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
0.062
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
6.8
DANN
Benign
0.39
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.54
T
MetaRNN
Benign
0.000072
T
MetaSVM
Benign
-0.72
T
PhyloP100
3.9
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
0.72
N
REVEL
Uncertain
0.31
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Vest4
0.044
MPC
0.076
ClinPred
0.0037
T
GERP RS
4.9
gMVP
0.45
Mutation Taster
=99/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs8589; hg19: chr6-49403282; COSMIC: COSV51274081; API