rs104893851

Variant names:

• chr4-145639572-C-T
• rs104893851
• NM_172250.3:c.433C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:2
• Conservation: PhyloP100: 4.34
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblA type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 4-145639572-C-T is Pathogenic according to our data. Variant chr4-145639572-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3160.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
MMAA	NM_172250.3	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENST00000649156.2	NP_758454.1
MMAA	NM_001375644.1	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7		XP_011529986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7		NM_172250.3	ENSP00000497008.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151944 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000161 AC: 40 AN: 248412 AF XY: 0.000179

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 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.: 1 Cov.: 31 AF XY: 0.000401 AC XY: 290 AN XY: 723200

African (AFR) AF: 0.0000904 AC: 3 AN: 33190

American (AMR) AF: 0.0000453 AC: 2 AN: 44138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000317 AC: 27 AN: 85234

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.000486 AC: 539 AN: 1108490

Other (OTH) AF: 0.000532 AC: 32 AN: 60120

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151944 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74178

African (AFR) AF: 0.0000483 AC: 2 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000437

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:12 Other:2

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 21, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 15, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PVS1, PM2_Supporting, PM3_VeryStrong, PP4

Dec 18, 2018

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 24, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 08, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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.

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Jan 11, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3_Strong

not provided Pathogenic:7

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MMAA: PM3:Very Strong, PVS1, PM2:Supporting

Nov 04, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 05, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

May 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Methylmalonic acidemia Pathogenic:2

May 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 10, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PS1,PS4

MMAA-related disorder Pathogenic:1

Apr 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.0	.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		4.3
PROVEAN	Benign	0.0	.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.
Vest4		0.0
GERP RS		3.0
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

Other links and lift over

dbSNP: rs104893851; hg19: chr4-146560724; COSMIC: COSV55580062; COSMIC: COSV55580062;