rs796051993

Variant summary

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

The NM_172250.3(MMAA):c.593_596del(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:10O: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:

(HGNC:):

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/exons	MANE
MMAA	NM_172250.3 linkuse as main transcript	c.593_596del	p.Thr198SerfsTer6	frameshift_variant	4/7	ENST00000649156.2
MMAA	NM_001375644.1 linkuse as main transcript	c.593_596del	p.Thr198SerfsTer6	frameshift_variant	4/7
MMAA	XM_011531684.4 linkuse as main transcript	c.593_596del	p.Thr198SerfsTer6	frameshift_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2 linkuse as main transcript	c.593_596del	p.Thr198SerfsTer6	frameshift_variant	4/7		NM_172250.3	P1
	ENST00000504555.1 linkuse as main transcript	n.254-3189_254-3186del		intron_variant, non_coding_transcript_variant		5

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:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 26, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 11, 2019	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2014	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). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MMAA: PM3:Very Strong, PVS1, PM2 -

Methylmalonic acidemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2018	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. -

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