rs104893851

Positions:

chr4-145639572-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_172250.3(MMAA):c.433C>T(p.Arg145*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000393 in 1,607,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

MMAA
NM_172250.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:2

Conservation

PhyloP100: 4.34

Variant links:

Genes affected

MMAA (HGNC:18871): (metabolism of cobalamin associated A) The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMAA links:

MMAA (HGNC:):

MMAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-145639572-C-T is Pathogenic according to our data. Variant chr4-145639572-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-145639572-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAA	NM_172250.3 linkuse as main transcript	c.433C>T	p.Arg145*	stop_gained	2/7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 linkuse as main transcript	c.433C>T	p.Arg145*	stop_gained	2/7		NP_001362573.1
MMAA	XM_011531684.4 linkuse as main transcript	c.433C>T	p.Arg145*	stop_gained	2/7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 linkuse as main transcript	c.433C>T	p.Arg145*	stop_gained	2/7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

151944

Hom.:

Cov.:

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

248412

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

134236

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000235

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000416

AC:

606

AN:

1455800

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

290

AN XY:

723200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000904

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000317

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000486

Gnomad4 OTH exome

AF:

0.000532

GnomAD4 genome

AF:

0.000171

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74178

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:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000331

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:12Other:2

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 1006. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 11, 2022	PVS1, PM3_Strong -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 08, 2015	The heterozygous variant in the MMAA gene (c.433C>T; p.Arg145*) is considered a pathogenic variant. This change represents a rare premature truncation resulting in a product 1/3 of the expected length with the last ~ 273 amino acids being truncated off. This variant has been seen previously by Yang et al (PMID: 15308131) in a one individual in a Japanese affected individuals. In the ExAC dataset this variant was seen on 19 alleles out of 121038 tested, with all tested individuals being heterozygous for the change. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg145*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs104893851, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15308131, 15523652, 16247646, 17957493, 23026888, 26270765, 27591164). ClinVar contains an entry for this variant (Variation ID: 3160). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_172250.2(MMAA):c.433C>T(R145) is classified as pathogenic in the context of methylmalonic acidemia, cblA type. Sources cited for classification include the following: PMID 15523652. Classification of NM_172250.2(MMAA):c.433C>T(R145) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 18, 2018	The variant NM_172250.3:c.433C>T (p.Arg145Ter) in exon-2 of MMAA gene has been seen in heterozygous status. It is a nonsense variant that results in a stop codon and premature truncation of the protein. This variant has not been reported in the 1000 Genomes database and has a minor allele frequency of 0.02% in the ExAc database. The in-silico prediction of this variant is damaging by MutationTaster2. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Oct 15, 2024	ACMG: PVS1, PM2_Supporting, PM3_VeryStrong, PP4 -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2019	DNA sequence analysis of the MMAA gene demonstrated a sequence change, c.433C>T, which results in the creation of a premature stop codon at amino acid position 145, p.Arg145*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MMAA protein with potentially abnormal function. This sequence change has previously been described in multiple individuals with methylmalonic acidemia in a homozygous or a compound heterozygous state (PMIDs: 15308131, 15523652, 23026888). This sequence change has been described in the gnomAD database with a low population frequency of 0.016% (dbSNP rs104893851). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 04, 2022	The MMAA c.433C>T (p.Arg145Ter) nonsense variant results in the substitution of arginine at amino acid position 145 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.433C>T variant was identified in a homozygous state in at least 13 individuals, and in a compound heterozygous state in at least 15 individuals with methylmalonic aciduria (PMID: 15523652; PMID: 22614770; PMID: 35618652). The c.433C>T variant is reported at a frequency of 0.000353 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.433C>T (p.Arg145Ter) variant is classified as pathogenic for methylmalonic aciduria, cblA type. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15781192, 24095221, 16247646, 26270765, 17957493, 28497574, 26370686, 25087612, 27591164, 30609409, 30712249, 31589614, 32754920, 15523652, 23026888, 15308131) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	MMAA: PM3:Very Strong, PVS1, PM2:Supporting -

Methylmalonic acidemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2017	The p.Arg145X (NM_172250.2 c.433C>T) variant in MMAA has been reported in 2 het erozygous, 12 homozygous (2 of which were consanguineous) and 10 compound hetero zygous individuals with methylmalonic acidemia (Lerner-Ellis 2004, Yang 2004, Ha armann 2013, and Devi 2017). This variant has also been reported in ClinVar (Var iation ID#3160) as pathogenic by multiple laboratories. This variant has been id entified in 0.04% (6/16350) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104893851). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant lead s to a premature termination codon at position 145, which is predicted to lead t o a truncated or absent protein. Biallelic loss of function of the MMAA gene has been associated with methylmalonic acidemia. In summary, this variant meets cr iteria to be classified as pathogenic for methylmalonic acidemia in an autosomal recessive manner based upon its biallelic occurrence in individuals with this d isease and predicted null effect on the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2016	Variant summary: MMAA c.433C>T variant results in a premature termination at codon 145 (274 amino acids from the end of the protein), predicted to cause a truncated or absent MMAA protein, which is a commonly known mechanism for methylmalonic academia. Mutation Taster predicts a damaging outcome for this variant; this predictions is supported by functional studies showing that patients homozygous for R145X have a "reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity" (10-29% of WT activity). This variant is found in 19/119564 control chromosomes at a frequency of 0.0001589, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0018257). The variant of interest has been reported in many patients from the literature, and R145X is a common disease variant that has been reported to represent 45% of pathogenic MMAA alleles (Lerner-Ellis et al. 2004). In addition, several clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Oct 10, 2022

ACMG categories: PVS1,PS1,PS4 -

MMAA-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2023

The MMAA c.433C>T variant is predicted to result in premature protein termination (p.Arg145*). This variant is one of the most commonly reported variants causative for methylmalonic acidemia, cblA type (for example, see Lerner-Ellis et al. 2004. PubMed ID: 15523652; Yang et al. 2004. PubMed ID: 15308131; Hörster et al. 2020. PubMed ID: 32754920). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560724-C-T). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

Vest4

0.90, 0.90

GERP RS

3.0

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

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