dbSNP rs796051992: MMAA:p.Tyr129* (chr4-145639526-C-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.387C>A(p.Tyr129*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MMAA
NM_172250.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.02

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:

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 4-145639526-C-A is Pathogenic according to our data. Variant chr4-145639526-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 203814.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 link	c.387C>A	p.Tyr129*	stop_gained	Exon 2 of 7	ENST00000649156.2	NP_758454.1	Q8IVH4
MMAA	NM_001375644.1 link	c.387C>A	p.Tyr129*	stop_gained	Exon 2 of 7		NP_001362573.1
MMAA	XM_011531684.4 link	c.387C>A	p.Tyr129*	stop_gained	Exon 2 of 7		XP_011529986.1	Q8IVH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAA	ENST00000649156.2 link	c.387C>A	p.Tyr129*	stop_gained	Exon 2 of 7		NM_172250.3	ENSP00000497008.1		Q8IVH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250652

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461022

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblA type

Pathogenic:6

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 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.Tyr129*) 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 (rs796051992, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25959030). ClinVar contains an entry for this variant (Variation ID: 203814). For these reasons, this variant has been classified as Pathogenic. -

Jan 12, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jun 06, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Y129X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was homozygous for the Y129X variant (Lerner-Ellis et al., 2004). This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. -

MMAA-related disorder

Pathogenic:1

Jan 23, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MMAA c.387C>A variant is predicted to result in premature protein termination (p.Tyr129*). This variant has been reported, in the homozygous state or heterozygous state with a second causative MMAA variant, in at least two cblA type methylmalonic acidemia patients (MMA) (Lerner-Ellis et al 2004. PubMed ID: 15523652; Table S1 - Manoli et al. 2016. PubMed ID: 26270765; Hörster et al. 2020. PubMed ID: 32754920). Other loss-of-function variants surrounding this region have also been reported to be causative for MMA. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560678-C-A). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Methylmalonic acidemia

Pathogenic:1

May 09, 2021

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.387C>A (p.Tyr129X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250652 control chromosomes. c.387C>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Lerner-Ellis_2004, Horster_2021). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

Vest4

0.84, 0.85

GERP RS

3.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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