rs115923556

chr6-49459262-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000255.4(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. 12/18 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 NM_000255.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 3.19

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 -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: {Uncertain_significance=4, Likely_benign=3}. 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.205A>G	p.Ile69Val	missense_variant	2/13	ENST00000274813.4
MMUT	XM_005249143.4	c.205A>G	p.Ile69Val	missense_variant	2/13

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152184 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.00204 AC XY: 277 AN XY: 135908

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.: 13 Cov.: 31 AF XY: 0.00260 AC XY: 1889 AN XY: 727240

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.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74474

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.: 2

Bravo AF: 0.00187

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -
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	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2022	- -
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, 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. -

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 condition Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	13
Dann	Benign	0.69
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.54
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.78
MVP		0.78
MPC		0.080
ClinPred		0.0067	T
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

Other links and lift over

dbSNP: rs115923556; hg19: chr6-49426975; COSMIC: COSV51278068; COSMIC: COSV51278068;