rs1446389693

Positions:

chr6-49457790-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.654A>C(p.Gln218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,404 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.457

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 6-49457790-T-G is Pathogenic according to our data. Variant chr6-49457790-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49457790-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.654A>C	p.Gln218His	missense_variant	3/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4 linkuse as main transcript	c.654A>C	p.Gln218His	missense_variant	3/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.654A>C	p.Gln218His	missense_variant	3/13	1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251050

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461198

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 218 of the MUT protein (p.Gln218His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 10923046, 16281286). This variant is also known as 730A>C. ClinVar contains an entry for this variant (Variation ID: 551243). 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%. Experimental studies have shown that this missense change affects MUT function (PMID: 25125334). For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 30, 2017	- -

MMUT-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The MMUT c.654A>C variant is predicted to result in the amino acid substitution p.Gln218His. This variant has been reported in the homozygous state or heterozygous state with a second pathogenic MMUT variant in individuals with methylmalonic acidemia (Fuchshuber et al. 2000. PubMed ID: 10923046; Worgan et al. 2006. PubMed ID: 16281286; Hörster et al. 2020. PubMed ID: 32754920). The p.Gln218 amino acid is located within the enzyme substrate binding channel, and in experimental studies the p.Gln218His substitution lead to severely reduced enzyme activity (Forny et al. 2014. PubMed ID: 25125334). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-49425503-T-G). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.093

FATHMM_MKL

Benign

0.58

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.97

MutPred

0.94

Gain of glycosylation at T216 (P = 0.089);

MVP

0.97

MPC

0.47

ClinPred

1.0

GERP RS

-0.98

gMVP

0.99

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over