rs757548934

Positions:

• chr4-145651070-C-T

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.742C>T​(p.Gln248Ter) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMAA NM_172250.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.42

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]

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 4-145651070-C-T is Pathogenic according to our data. Variant chr4-145651070-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 496554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-145651070-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAA	NM_172250.3	c.742C>T	p.Gln248Ter	stop_gained	5/7	ENST00000649156.2
MMAA	NM_001375644.1	c.742C>T	p.Gln248Ter	stop_gained	5/7
MMAA	XM_011531684.4	c.742C>T	p.Gln248Ter	stop_gained	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAA	ENST00000649156.2	c.742C>T	p.Gln248Ter	stop_gained	5/7		NM_172250.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251458 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

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 Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblA type Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2023	ClinVar contains an entry for this variant (Variation ID: 496554). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25748407, 28497574). This variant is present in population databases (rs757548934, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln248*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 09, 2024	- -

Methylmalonic acidemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 30, 2016

Variant summary: The MMAA c.742C>T (p.Gln248X) variant results in a premature termination codon, predicted to cause a truncated or absent MMAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The truncated protein is expected to remove the 170 amino acids in the C-terminus, which includes part of the P-loop containing nucleoside triphosphate hydrolase domain. One in silico tool predicts a damaging outcome for this variant. Xiong_2015 predicted a large splicing change induced by this variant. However, this change was not predicted by 5/5 splice prediction tools. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4/121506 control chromosomes at a frequency of 0.0000329 (all alleles are from East Asian subpopuation), which does not exceed the estimated maximal expected allele frequency of a pathogenic MMAA variant (0.0018257). This variant has been reported in at least two patients. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;D
Vest4		0.95, 0.95
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757548934; hg19: chr4-146572222;