Genetic Variant MMAB:p.Arg190Ser (chr12-109561056-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_052845.4(MMAB):c.568C>A(p.Arg190Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000677 in 147,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R190H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 30)

Consequence

MMAB
NM_052845.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.15

Publications

9 publications found

Variant links:

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MMAB Gene-Disease associations (from GenCC):

methylmalonic aciduria, cblB type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

MMAB links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_052845.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-109561055-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 203819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052845.4. 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
	MMAB	NM_052845.4	MANE Select	c.568C>A	p.Arg190Ser	missense	Exon 7 of 9	NP_443077.1
	MMAB	NR_038118.2		n.679C>A		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.568C>A	p.Arg190Ser	missense	Exon 7 of 9	ENSP00000445920.1
MMAB	ENST00000878519.1		c.631C>A	p.Arg211Ser	missense	Exon 8 of 10	ENSP00000548578.1
MMAB	ENST00000878520.1		c.568C>A	p.Arg190Ser	missense	Exon 7 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes

AF:

0.00000677

AC:

AN:

147622

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000677

AC:

AN:

147622

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71806

show subpopulations

African (AFR)

AF:

0.0000248

AC:

AN:

40346

American (AMR)

AF:

0.00

AC:

AN:

14698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

4648

South Asian (SAS)

AF:

0.00

AC:

AN:

4366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66954

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

PhyloP100

7.2

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.92

MutPred

0.97

Loss of MoRF binding (P = 0.0182)

MVP

1.0

MPC

0.89

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Mutation Taster

=4/96

disease causing

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over