rs887126161

chr6-49448840-G-A

Variant summary

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

The NM_000255.4(MMUT):c.1420C>T(p.Arg474Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000753 in 1,461,044 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: 0.0000075 (0 hom.)
• Consequence: MMUT NM_000255.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.52

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types 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 6-49448840-G-A is Pathogenic according to our data. Variant chr6-49448840-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 554873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49448840-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.1420C>T	p.Arg474Ter	stop_gained	7/13	ENST00000274813.4
MMUT	XM_005249143.4	c.1420C>T	p.Arg474Ter	stop_gained	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1420C>T	p.Arg474Ter	stop_gained	7/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251244 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461044 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726872

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2023

This sequence change creates a premature translational stop signal (p.Arg474*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria (PMID: 15643616, 16281286). ClinVar contains an entry for this variant (Variation ID: 554873). For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 08, 2017

- -

Methylmalonic acidemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 20, 2019

Variant summary: MUT c.1420C>T (p.Arg474X) 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 251244 control chromosomes (gnomAD). c.1420C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (e.g. Acquaviva_2015, Forny_2016, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. Biochemical studies report low incorporation of propionate and low MUT enzyme activity for cells with the variant and assign mut0 class (Forny_2016, Worgan_2006). Two ClinVar submitters (evaluation after 2014) cite 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	0.56	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		5.1

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: rs887126161; hg19: chr6-49416553;