6-49444720-C-T

Position:

chr6-49444720-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000274813.4(MMUT):c.1595G>A(p.Arg532His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,252 control chromosomes in the GnomAD database, including 101,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R532C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 7467 hom., cov: 31)

Exomes 𝑓: 0.35 ( 93675 hom. )

Consequence

MMUT
ENST00000274813.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0150

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071864724).

BP6

Variant 6-49444720-C-T is Benign according to our data. Variant chr6-49444720-C-T is described in ClinVar as [Benign]. Clinvar id is 92681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49444720-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.1595G>A	p.Arg532His	missense_variant	9/13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 linkuse as main transcript	c.1595G>A	p.Arg532His	missense_variant	9/13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.1595G>A	p.Arg532His	missense_variant	9/13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45876

AN:

151788

Hom.:

7460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.349

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.288

GnomAD3 exomes

AF:

0.316

AC:

79267

AN:

250824

Hom.:

13453

AF XY:

0.323

AC XY:

43832

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.234

Gnomad SAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.317

GnomAD4 exome

AF:

0.354

AC:

516885

AN:

1460346

Hom.:

93675

Cov.:

AF XY:

0.354

AC XY:

257161

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.188

Gnomad4 ASJ exome

AF:

0.330

Gnomad4 EAS exome

AF:

0.230

Gnomad4 SAS exome

AF:

0.357

Gnomad4 FIN exome

AF:

0.369

Gnomad4 NFE exome

AF:

0.371

Gnomad4 OTH exome

AF:

0.333

GnomAD4 genome

AF:

0.302

AC:

45893

AN:

151906

Hom.:

7467

Cov.:

AF XY:

0.301

AC XY:

22369

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.203

Gnomad4 AMR

AF:

0.230

Gnomad4 ASJ

AF:

0.349

Gnomad4 EAS

AF:

0.219

Gnomad4 SAS

AF:

0.371

Gnomad4 FIN

AF:

0.374

Gnomad4 NFE

AF:

0.368

Gnomad4 OTH

AF:

0.289

Alfa

AF:

0.348

Hom.:

14625

Bravo

AF:

0.282

TwinsUK

AF:

0.383

AC:

1421

ALSPAC

AF:

0.365

AC:

1408

ESP6500AA

AF:

0.211

AC:

929

ESP6500EA

AF:

0.366

AC:

3148

ExAC

AF:

0.322

AC:

39130

Asia WGS

AF:

0.327

AC:

1139

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.337

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 32% of total chromosomes in ExAC -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2017	Variant summary: The MUT c.1595G>A (p.Arg532His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 39104/121218 control chromosomes (6814 homozygotes) at a frequency of 0.3225924, which is approximately 134 times the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	This variant is associated with the following publications: (PMID: 19744961, 23754956, 27591164) -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.035

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

0.58

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.43

Sift

Benign

0.056

Sift4G

Benign

0.072

Vest4

0.12

MPC

0.13

ClinPred

0.014

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.26

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