rs115923556

Positions:

chr6-49459262-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000274813.4(MMUT):c.205A>G(p.Ile69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,614,184 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I69M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 13 hom. )

Consequence

MMUT
ENST00000274813.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 3.19

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027026802).

BP6

Variant 6-49459262-T-C is Benign according to our data. Variant chr6-49459262-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235300.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr6-49459262-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152302) while in subpopulation NFE AF= 0.0039 (265/68024). AF 95% confidence interval is 0.00351. There are 2 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.205A>G	p.Ile69Val	missense_variant	2/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4 linkuse as main transcript	c.205A>G	p.Ile69Val	missense_variant	2/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.205A>G	p.Ile69Val	missense_variant	2/13	1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00202

AC:

507

AN:

251472

Hom.:

AF XY:

0.00204

AC XY:

277

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.00334

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00263

AC:

3851

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

1889

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.00361

Gnomad4 NFE exome

AF:

0.00309

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00232

AC:

353

AN:

152302

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00442

Gnomad4 NFE

AF:

0.00390

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00306

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MUT p.Ile69Val variant was identified in dbSNP (ID: rs115923556), LOVD 3.0, ClinVar (classified as likely benign by Invitae and as a VUS by EGL Genetics and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and Cosmic (FATHMM predicted pathogenic; score=0.91). The variant was also identified in control databases in 602 of 282866 chromosomes (2 homozygous) at a frequency of 0.002128 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 458 of 129172 chromosomes (freq: 0.003546), European (Finnish) in 85 of 25120 chromosomes (freq: 0.003384), Other in 15 of 7228 chromosomes (freq: 0.002075), African in 14 of 24968 chromosomes (freq: 0.000561), South Asian in 16 of 30616 chromosomes (freq: 0.000523) and Latino in 14 of 35440 chromosomes (freq: 0.000395), while the variant was not observed in the Ashkenazi Jewish and East Asian populations. The I69V variant was identified in 1/25 patients with isolated methylmalonic acidemia (freq=0.02) but was suggested to be a polymorphism (Martinez_2005_PMID:15781192). This variant was also identified in the heterozygous state in 1/160 cell lines from patients with the mitochondrial enzyme methylmalonyl CoA mutase (MCM) deficiency (freq=0.003) but was also suggested to be a polymorphism (Worgan_2006_PMID:16281286). The p.Ile69 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2022	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

MMUT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.69

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.061

MetaRNN

Benign

0.027

MetaSVM

Uncertain

-0.17

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.54

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.78

MVP

0.78

MPC

0.080

ClinPred

0.0067

GERP RS

2.0

gMVP

0.61

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