NM_000255.4:c.2011A>G

Variant names:

• chr6-49435569-T-C
• rs8589
• NM_000255.4:c.2011A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(MMUT):​c.2011A>G​(p.Ile671Val) variant causes a missense change. The variant allele was found at a frequency of 0.606 in 1,613,526 control chromosomes in the GnomAD database, including 300,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.59 (26674 hom., cov: 33)
  • Exomes 𝑓: 0.61 (273683 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.90
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• vitamin B12-unresponsive methylmalonic acidemia type mut-

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• vitamin B12-unresponsive methylmalonic acidemia type mut0

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000255.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 150 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.22855 (below the threshold of 3.09). Trascript score misZ: 1.0842 (below the threshold of 3.09). GenCC associations: The gene is linked to vitamin B12-unresponsive methylmalonic acidemia type mut-, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut0.
• BP4: Computational evidence support a benign effect (MetaRNN=7.249867E-5).
• BP6: Variant 6-49435569-T-C is Benign according to our data. Variant chr6-49435569-T-C is described in ClinVar as Benign. ClinVar VariationId is 92685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.2011A>G	p.Ile671Val	missense	Exon 12 of 13	NP_000246.2	P22033

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.2011A>G	p.Ile671Val	missense	Exon 12 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.2011A>G	p.Ile671Val	missense	Exon 12 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.2011A>G	p.Ile671Val	missense	Exon 12 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89383 AN: 151988 Hom.: 26651 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.562 AC: 140906 AN: 250646 AF XY: 0.573

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.593

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.608 AC: 888933 AN: 1461420 Hom.: 273683 Cov.: 55 AF XY: 0.610 AC XY: 443448 AN XY: 726986

African (AFR) AF: 0.586 AC: 19622 AN: 33478

American (AMR) AF: 0.331 AC: 14771 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14374 AN: 26136

East Asian (EAS) AF: 0.439 AC: 17438 AN: 39688

South Asian (SAS) AF: 0.641 AC: 55289 AN: 86232

European-Finnish (FIN) AF: 0.599 AC: 31981 AN: 53390

Middle Eastern (MID) AF: 0.556 AC: 3202 AN: 5754

European-Non Finnish (NFE) AF: 0.626 AC: 696315 AN: 1111710

Other (OTH) AF: 0.595 AC: 35941 AN: 60376

GnomAD4 genome AF: 0.588 AC: 89445 AN: 152106 Hom.: 26674 Cov.: 33 AF XY: 0.583 AC XY: 43327 AN XY: 74362

African (AFR) AF: 0.592 AC: 24568 AN: 41472

American (AMR) AF: 0.435 AC: 6651 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1958 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2383 AN: 5180

South Asian (SAS) AF: 0.650 AC: 3129 AN: 4816

European-Finnish (FIN) AF: 0.602 AC: 6382 AN: 10594

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42485 AN: 67980

Other (OTH) AF: 0.553 AC: 1168 AN: 2112

Alfa AF: 0.599 Hom.: 79528

Bravo AF: 0.568

TwinsUK AF: 0.636 AC: 2360

ALSPAC AF: 0.626 AC: 2411

ESP6500AA AF: 0.588 AC: 2590

ESP6500EA AF: 0.617 AC: 5304

ExAC AF: 0.574 AC: 69652

Asia WGS AF: 0.547 AC: 1906 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.600

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (6)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.8
DANN	Benign	0.39
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.000073	T
MetaSVM	Benign	-0.72	T
PhyloP100		3.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.72	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.044
MPC		0.076
ClinPred		0.0037	T
GERP RS		4.9
gMVP		0.45
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8589; hg19: chr6-49403282; COSMIC: COSV51274081;