6-49451673-C-T

Position:

• chr6-49451673-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

The NM_000255.4(MMUT):​c.1125G>A​(p.Met375Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,918 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 7.91

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000255.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.14153054).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (237/152276) while in subpopulation NFE AF= 0.00309 (210/68032). AF 95% confidence interval is 0.00274. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.1125G>A	p.Met375Ile	missense_variant	6/13	ENST00000274813.4
MMUT	XM_005249143.4	c.1125G>A	p.Met375Ile	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1125G>A	p.Met375Ile	missense_variant	6/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 250982 Hom.: 0 AF XY: 0.00142 AC XY: 192 AN XY: 135630

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00178 AC: 2599 AN: 1461642 Hom.: 3 Cov.: 31 AF XY: 0.00175 AC XY: 1270 AN XY: 727134

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74466

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 17, 2022	The MMUT c.1125G>A; p.Met375Ile variant (rs148091558) is reported in the literature in individuals affected with multiple sclerosis, but is also found in healthy controls (Traboulsee 2017). This variant is also reported in ClinVar (Variation ID: 290321), and is found in the general population with an overall allele frequency of 0.16% (438/282374 alleles) in the Genome Aggregation Database. The methionine at codon 375 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.853). Due to limited information, the clinical significance of the p.Met375Ile variant is uncertain at this time. References: Traboulsee AL et al. Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis. Hum Genet. 2017 Jun;136(6):705-714. PMID: 28337550. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2022	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign in association with methylmalonic acidemia to our knowledge; This variant is associated with the following publications: (PMID: 28337550) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 27, 2019

- -

MMUT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.14	T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Vest4		0.91
MutPred		0.74		Gain of catalytic residue at M375 (P = 0.2503);
MVP		0.94
MPC		0.15
ClinPred		0.17	T
GERP RS		5.0
gMVP		0.97

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: rs148091558; hg19: chr6-49419386;