rs879253820

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000255.4(MMUT):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000343 in 1,457,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MMUT
NM_000255.4 start_lost

Scores

6
6
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.45

Publications

5 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: Pathogenic. The variant received 18 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 22 pathogenic variants. Next in-frame start position is after 79 codons. Genomic position: 49459232. Lost 0.104 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-49459465-A-G is Pathogenic according to our data. Variant chr6-49459465-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 222903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMUTNM_000255.4 linkc.2T>C p.Met1? start_lost Exon 2 of 13 ENST00000274813.4 NP_000246.2 P22033A0A024RD82B2R6K1
MMUTXM_005249143.4 linkc.2T>C p.Met1? start_lost Exon 2 of 13 XP_005249200.1 P22033A0A024RD82

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMUTENST00000274813.4 linkc.2T>C p.Met1? start_lost Exon 2 of 13 1 NM_000255.4 ENSP00000274813.3 P22033

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1457672
Hom.:
0
Cov.:
31
AF XY:
0.00000414
AC XY:
3
AN XY:
725320
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33450
American (AMR)
AF:
0.00
AC:
0
AN:
44674
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86178
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4948
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111938
Other (OTH)
AF:
0.00
AC:
0
AN:
60250
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1
Jan 27, 2025
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1
-
University Children's Hospital, University of Zurich
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

METHYLMALONIC ACIDURIA, mut(0) TYPE Pathogenic:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.53
CADD
Benign
22
DANN
Uncertain
0.99
Eigen
Benign
0.088
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.66
D
PhyloP100
6.5
PROVEAN
Benign
-0.72
N
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0040
D
Vest4
0.95
MutPred
1.0
Gain of catalytic residue at M1 (P = 0.0286);
MVP
0.99
ClinPred
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
gMVP
0.73
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879253820; hg19: chr6-49427178; API