Variant 6-49448861-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000274813.4(MMUT):c.1399C>T(p.Arg467Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000409 in 1,613,322 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: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

MMUT
ENST00000274813.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.32

Variant links:

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]

MMUT 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 6-49448861-G-A is Pathogenic according to our data. Variant chr6-49448861-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 495778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.1399C>T	p.Arg467Ter	stop_gained	7/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4 linkuse as main transcript	c.1399C>T	p.Arg467Ter	stop_gained	7/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.1399C>T	p.Arg467Ter	stop_gained	7/13	1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251284

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000995

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2018	The MUT c.1399C>T (p.Arg467Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been described in five studies in eight probands with classic methylmalonic acidemia (MMA), with one in a homozygous state and seven in a compound heterozygous state (Peters et al. 2002; Acquaviva et al. 2005; Worgan et al. 2006; DÃ¼ndar et al. 2012; Liu et al. 2012). The p.Arg467Ter variant was absent from 48 anonymous controls and is reported at a frequency of 0.001320 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies showed that six of the patients (one homozygote and five compound heterozygotes) carrying the p.Arg467Ter variant demonstrated zero enzyme activity ('mut0' phenotype) (Acquaviva et al. 2005). Based on the potential impact of truncating variants and presence in affected individuals, the p.Arg467Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 01, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change creates a premature translational stop signal (p.Arg467*) 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 (rs774159791, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 12402345, 16281286, 22727635, 26790480). ClinVar contains an entry for this variant (Variation ID: 495778). 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 acidemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 11, 2016

Variant summary: The MUT c.1399C>T variant results into nonsense mutation in exon 7 predicted to cause a loss of protein function due to production of a truncated protein or nonsense-mediated mRNA decay. It was exclusively observed in the Non-Finnish European sub-cohort of the ExAC project at an allele frequency of 0.0015%, which does not exceed the maximal expected allele frequency of a disease-causing MUT allele (0.24%). In the literature, the variant was observed in several patients with methylmalonic aciduria in compound heterozygosity with other truncating as well as missense variants, consistent with a disease-causing nature. Two reputable databases as well as one clinical lab has classified this variant as pathogenic. Considering all evidence, the variant has been classified as a Disease Variant/Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

Vest4

0.99

GERP RS

3.9

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