Genetic Variant NM_000255.4:c.1105C>T (chr6-49451693-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.1105C>T(p.Arg369Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 10.0

Publications

14 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), 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

MMUT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000255.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-49451692-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 203846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 6-49451693-G-A is Pathogenic according to our data. Variant chr6-49451693-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 218989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.1105C>T	p.Arg369Cys	missense	Exon 6 of 13	NP_000246.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MMUT	ENST00000274813.4	TSL:1 MANE Select	c.1105C>T	p.Arg369Cys	missense	Exon 6 of 13	ENSP00000274813.3
MMUT	ENST00000878060.1		c.1105C>T	p.Arg369Cys	missense	Exon 6 of 13	ENSP00000548119.1
MMUT	ENST00000878062.1		c.1105C>T	p.Arg369Cys	missense	Exon 6 of 13	ENSP00000548121.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

250668

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461472

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111694

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000975

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Methylmalonic acidemia (1)

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency (1)

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.91

PhyloP100

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.98

MVP

1.0

MPC

0.57

ClinPred

1.0

GERP RS

5.0

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -13

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over