rs115923556

Variant names:

• chr6-49459262-T-C
• rs115923556
• NM_000255.4:c.205A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 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. 13/20 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:5
• Conservation: PhyloP100: 3.19
• Publications: 9 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 -12 ACMG points.

• 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 methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut-, vitamin B12-unresponsive methylmalonic acidemia type mut0.
• 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 VariationId is 235300.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.205A>G	p.Ile69Val	missense	Exon 2 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.205A>G	p.Ile69Val	missense	Exon 2 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.205A>G	p.Ile69Val	missense	Exon 2 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.205A>G	p.Ile69Val	missense	Exon 2 of 13	ENSP00000548121.1

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

GnomAD2 exomes AF: 0.00202 AC: 507 AN: 251472 AF XY: 0.00204

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 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

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86258

European-Finnish (FIN) AF: 0.00361 AC: 193 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00309 AC: 3439 AN: 1112002

Other (OTH) AF: 0.00209 AC: 126 AN: 60394

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74474

African (AFR) AF: 0.000649 AC: 27 AN: 41574

American (AMR) AF: 0.000523 AC: 8 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00283 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	-	1	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)
-	1	-	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (1)
-	-	1	MMUT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.2
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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

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