6-49444720-C-G

Variant names:

• chr6-49444720-C-G
• rs1141321
• NM_000255.4:c.1595G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000255.4(MMUT):​c.1595G>C​(p.Arg532Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R532H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 61 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3198474).

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.1595G>C	p.Arg532Pro	missense	Exon 9 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.1595G>C	p.Arg532Pro	missense	Exon 9 of 13	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.1595G>C	p.Arg532Pro	missense	Exon 9 of 13	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.1595G>C	p.Arg532Pro	missense	Exon 9 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.91
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.62	D
PhyloP100		-0.015
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.55
Sift	Benign	0.089	T
Sift4G	Benign	0.085	T
Vest4		0.39
MutPred		0.61		Gain of catalytic residue at R532 (P = 0.002)
MVP		0.87
MPC		0.15
ClinPred		0.34	T
GERP RS		1.4
gMVP		0.80
Mutation Taster		=65/35	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: rs1141321; hg19: chr6-49412433;