rs2229384

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000255.4(MMUT):c.636G>A(p.Lys212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 1,611,684 control chromosomes in the GnomAD database, including 299,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26299 hom., cov: 32)

Exomes 𝑓: 0.61 ( 273682 hom. )

Consequence

MMUT
NM_000255.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.669

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 6-49457808-C-T is Benign according to our data. Variant chr6-49457808-C-T is described in ClinVar as [Benign]. Clinvar id is 92687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49457808-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.669 with no splicing effect.

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/exons	MANE	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.636G>A	p.Lys212=	synonymous_variant	3/13	ENST00000274813.4
MMUT	XM_005249143.4 linkuse as main transcript	c.636G>A	p.Lys212=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.636G>A	p.Lys212=	synonymous_variant	3/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88723

AN:

151784

Hom.:

26275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.576

Gnomad AMI

AF:

0.635

Gnomad AMR

AF:

0.434

Gnomad ASJ

AF:

0.564

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.626

Gnomad OTH

AF:

0.554

GnomAD3 exomes

AF:

0.562

AC:

140894

AN:

250846

Hom.:

41158

AF XY:

0.572

AC XY:

77617

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.578

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.545

Gnomad EAS exome

AF:

0.485

Gnomad SAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.593

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.609

AC:

888298

AN:

1459782

Hom.:

273682

Cov.:

AF XY:

0.610

AC XY:

443301

AN XY:

726320

show subpopulations

Gnomad4 AFR exome

AF:

0.572

Gnomad4 AMR exome

AF:

0.330

Gnomad4 ASJ exome

AF:

0.550

Gnomad4 EAS exome

AF:

0.458

Gnomad4 SAS exome

AF:

0.642

Gnomad4 FIN exome

AF:

0.599

Gnomad4 NFE exome

AF:

0.626

Gnomad4 OTH exome

AF:

0.596

GnomAD4 genome

AF:

0.585

AC:

88790

AN:

151902

Hom.:

26299

Cov.:

AF XY:

0.580

AC XY:

43030

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.576

Gnomad4 AMR

AF:

0.433

Gnomad4 ASJ

AF:

0.564

Gnomad4 EAS

AF:

0.478

Gnomad4 SAS

AF:

0.650

Gnomad4 FIN

AF:

0.604

Gnomad4 NFE

AF:

0.625

Gnomad4 OTH

AF:

0.554

Alfa

AF:

0.601

Hom.:

19579

Bravo

AF:

0.564

Asia WGS

AF:

0.555

AC:

1931

AN:

3478

EpiCase

AF:

0.606

EpiControl

AF:

0.599

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: 57% of total chromosomes in ExAC -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

Cadd

Benign

4.4

Dann

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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