6-49444720-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(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 NM_000255.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0150

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 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	UniProt
MMUT	NM_000255.4	c.1595G>A	p.Arg532His	missense_variant	9/13	ENST00000274813.4
MMUT	XM_005249143.4	c.1595G>A	p.Arg532His	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1595G>A	p.Arg532His	missense_variant	9/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45876 AN: 151788 Hom.: 7460 Cov.: 31

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

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.: 35 AF XY: 0.354 AC XY: 257161 AN XY: 726516

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.: 31 AF XY: 0.301 AC XY: 22369 AN XY: 74214

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

Submissions by phenotype

not specified Benign:5

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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:5

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	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	Pars Genome Lab	Jun 19, 2021	- -
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	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -
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. -

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	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.035	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	0.58	D
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.43
Sift	Benign	0.056	T
Sift4G	Benign	0.072	T
Vest4		0.12
MPC		0.13
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs1141321; hg19: chr6-49412433; COSMIC: COSV51272702;