NM_000255.4:c.1495G>A

Variant names:

• chr6-49447735-C-T
• rs2229385
• NM_000255.4:c.1495G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(MMUT):​c.1495G>A​(p.Ala499Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,609,812 control chromosomes in the GnomAD database, including 9,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A499P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (818 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8316 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.422
• Publications: 25 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 -19 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=0.001824379).
• BP6: Variant 6-49447735-C-T is Benign according to our data. Variant chr6-49447735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 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.1495G>A	p.Ala499Thr	missense	Exon 8 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.1495G>A	p.Ala499Thr	missense	Exon 8 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.1495G>A	p.Ala499Thr	missense	Exon 8 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.1495G>A	p.Ala499Thr	missense	Exon 8 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15706 AN: 151522 Hom.: 817 Cov.: 32

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0810

Gnomad ASJ AF: 0.0912

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0979 AC: 24502 AN: 250150 AF XY: 0.101

Gnomad AFR exome AF: 0.0980

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0809

Gnomad EAS exome AF: 0.0621

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.105 AC: 152988 AN: 1458188 Hom.: 8316 Cov.: 32 AF XY: 0.105 AC XY: 76279 AN XY: 725478

African (AFR) AF: 0.0955 AC: 3187 AN: 33374

American (AMR) AF: 0.0595 AC: 2661 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 2137 AN: 26070

East Asian (EAS) AF: 0.0813 AC: 3216 AN: 39534

South Asian (SAS) AF: 0.0982 AC: 8464 AN: 86164

European-Finnish (FIN) AF: 0.134 AC: 7151 AN: 53338

Middle Eastern (MID) AF: 0.128 AC: 737 AN: 5750

European-Non Finnish (NFE) AF: 0.108 AC: 119299 AN: 1109038

Other (OTH) AF: 0.102 AC: 6136 AN: 60232

GnomAD4 genome AF: 0.104 AC: 15719 AN: 151624 Hom.: 818 Cov.: 32 AF XY: 0.105 AC XY: 7748 AN XY: 74088

African (AFR) AF: 0.0992 AC: 4107 AN: 41390

American (AMR) AF: 0.0808 AC: 1232 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 316 AN: 3464

East Asian (EAS) AF: 0.0685 AC: 353 AN: 5154

South Asian (SAS) AF: 0.0900 AC: 433 AN: 4810

European-Finnish (FIN) AF: 0.141 AC: 1487 AN: 10524

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7383 AN: 67734

Other (OTH) AF: 0.105 AC: 220 AN: 2102

Alfa AF: 0.104 Hom.: 2766

Bravo AF: 0.0997

TwinsUK AF: 0.105 AC: 388

ALSPAC AF: 0.114 AC: 439

ESP6500AA AF: 0.0988 AC: 435

ESP6500EA AF: 0.106 AC: 908

ExAC AF: 0.0988 AC: 11990

Asia WGS AF: 0.0640 AC: 220 AN: 3476

EpiCase AF: 0.111

EpiControl AF: 0.113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (4)
-	-	3	not provided (3)
-	-	1	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.9
DANN	Benign	0.95
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	-0.25	T
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.19
Sift	Benign	0.085	T
Sift4G	Benign	0.17	T
Vest4		0.047
MPC		0.088
ClinPred		0.0046	T
GERP RS		-2.1
gMVP		0.27
Mutation Taster		=90/10	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: rs2229385; hg19: chr6-49415448; COSMIC: COSV51274129;