rs140356252

chr4-145646073-T-Achr4-145646073-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_172250.3(MMAA):c.650T>A(p.Leu217Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L217L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMAA NM_172250.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.48

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]

(HGNC:):

ACMG classification

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 4-145646073-T-A is Pathogenic according to our data. Variant chr4-145646073-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.650T>A	p.Leu217Ter	stop_gained	4/7	ENST00000649156.2
MMAA	NM_001375644.1	c.650T>A	p.Leu217Ter	stop_gained	4/7
MMAA	XM_011531684.4	c.650T>A	p.Leu217Ter	stop_gained	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.650T>A	p.Leu217Ter	stop_gained	4/7		NM_172250.3	P1
	ENST00000504555.1	n.254-3246A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 218976). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 15308131). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu217*) 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). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 25, 2018	- -

Methylmalonic acidemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 23, 2021

Variant summary: MMAA c.650T>A (p.Leu217X) 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 was absent in 251418 control chromosomes. c.650T>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (e.g. Yang_2004, Tang_2020). These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely 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	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	38
Dann	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;D
Vest4		0.90, 0.90
GERP RS		5.4

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

Other links and lift over

dbSNP: rs140356252; hg19: chr4-146567225;