6-49451690-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):​c.1108A>C​(p.Thr370Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,170 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

MMUT
NM_000255.4 missense

Scores

14
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_000255.4 (MMUT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a helix (size 14) in uniprot entity MUTA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000255.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 6-49451690-T-G is Pathogenic according to our data. Variant chr6-49451690-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203847.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.1108A>C p.Thr370Pro missense_variant Exon 6 of 13 ENST00000274813.4 NP_000246.2 P22033A0A024RD82B2R6K1
MMUTXM_005249143.4 linkc.1108A>C p.Thr370Pro missense_variant Exon 6 of 13 XP_005249200.1 P22033A0A024RD82

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMUTENST00000274813.4 linkc.1108A>C p.Thr370Pro missense_variant Exon 6 of 13 1 NM_000255.4 ENSP00000274813.3 P22033

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250768
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135540
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000166
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not provided Pathogenic:3
Nov 25, 2015
Eurofins Ntd Llc (ga)
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 370 of the MUT protein (p.Thr370Pro). This variant is present in population databases (rs368790885, gnomAD 0.01%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 16281286; Invitae). ClinVar contains an entry for this variant (Variation ID: 203847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Apr 11, 2017
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The T370P missense variant in the MUT gene has been reported previously in association with methylmalonic acidemia (MMA) (Worgan et al., 2006). The T370P variant was identified on 2/58 (3.4%) MUT alleles in patients of African ancestry with MMA (Worgan et al., 2006). Based on currently available evidence, T370P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.91
MVP
1.0
MPC
0.35
ClinPred
1.0
D
GERP RS
5.0
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368790885; hg19: chr6-49419403; API