dbSNP rs796051993: MMAA:p.Thr198SerfsTer6 (chr4-145646012-ATGAC-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_172250.3(MMAA):c.593_596delCTGA(p.Thr198SerfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MMAA
NM_172250.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 9.35

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:

ENSG00000248356 (HGNC:):

ENSG00000248356 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 4-145646012-ATGAC-A is Pathogenic according to our data. Variant chr4-145646012-ATGAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 203815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-145646012-ATGAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAA	NM_172250.3 link	c.593_596delCTGA	p.Thr198SerfsTer6	frameshift_variant	Exon 4 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.593_596delCTGA	p.Thr198SerfsTer6	frameshift_variant	Exon 4 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.593_596delCTGA	p.Thr198SerfsTer6	frameshift_variant	Exon 4 of 7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.593_596delCTGA	p.Thr198SerfsTer6	frameshift_variant	Exon 4 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152204

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251392

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135868

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461754

Hom.:

AF XY:

0.0000344

AC XY:

AN XY:

727186

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:

0.0000374

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:7Other:1

Apr 11, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PS1,PP4. This variant was detected in homozygous state. -

Nov 26, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2024

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.Thr198Serfs*6) 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 (rs779859711, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with cblA-type methylmalonicaciduria (PMID: 15523652, 22614770, 28497574). This variant is also known as c.592_595del. ClinVar contains an entry for this variant (Variation ID: 203815). For these reasons, this variant has been classified as Pathogenic. -

Mar 06, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 18, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.593_596delCTGA deletion causes a frameshift starting with codon Threonine 198, changes this amino acid to a Serine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Thr198SerfsX6. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. c.593_596delCTGA has been reported previously in association with methylmalonic acidemia (MMA) (Lerner-Ellis et al., 2004; aka c.592_595delACTC). The variant is found in MMAA panel(s). -

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 -

Methylmalonic acidemia

Pathogenic:2

Dec 03, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr198SerfsX6 variant in MMAA has been reported in at least 5 compound het erozygous and 1 homozygous individuals with methylmalonic acidemia (Lerner-Ellis , 2004). It has also been identified in 10/129132 of European chromosomes by gno mAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 19 8 and leads to a premature termination codon 6 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Loss of funct ion of the MMAA gene is an established disease mechanism in autosomal recessive methylmalonic acidemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic acidemia. ACMG/AMP Criteria applied: PM2_Supportive, PVS1, PM3_Very Strong. -

Mar 19, 2018

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.593_596delCTGA (p.Thr198SerfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.7e-05 in 246266 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (3.7e-05 vs 0.0018), allowing no conclusion about variant significance. The c.593_596delCTGA variant has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia, both as a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-<30% of normal activity (Lerner-Ellis_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MMAA-related disorder

Pathogenic:1

May 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MMAA c.593_596delCTGA variant is predicted to result in a frameshift and premature protein termination (p.Thr198Serfs*6). This variant has been reported, in the homozygous or compound heterozygous state, in numerous individuals with methylmalonic acidemia, cblA type (e.g., Lerner-Ellis et al. 2004. PubMed ID: 15523652; Plessl et al. 2017. PubMed ID: 28497574; Kang et al. 2020. PubMed ID: 31622506). This variant has also been described in the literature as c.590_593del or c.592_595del. This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MMAA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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