12-109561067-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_052845.4(MMAB):c.557G>A(p.Arg186Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 1,610,882 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MMAB
NM_052845.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 5.67

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 14 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 chr12-109561067-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2954625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 12-109561067-C-T is Pathogenic according to our data. Variant chr12-109561067-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 552212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4 link	c.557G>A	p.Arg186Gln	missense_variant	Exon 7 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7 link	c.557G>A	p.Arg186Gln	missense_variant	Exon 7 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249300

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1458936

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111990

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000197

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000226

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Pathogenic:3Uncertain:1

May 30, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 13, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the MMAB protein (p.Arg186Gln). This variant is present in population databases (rs773059864, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of cobalamin B type methylmalonic aciduria (PMID: 16410054, 33453710, 33552909, 34796408). ClinVar contains an entry for this variant (Variation ID: 552212). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MMAB protein function with a positive predictive value of 80%. This variant disrupts the p.Arg186 amino acid residue in MMAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12471062, 16410054, 16439175, 19625202). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2021

Baumgartner lab, University Children's Hospital Zurich

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Methylmalonic acidemia

Pathogenic:1

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg186Gln variant in MMAB has been reported in the homozygous state in 3 individuals with methylmalonic acidemia (Lerner-Ellis 2006 PMID: 16410054, Kiykim 2021 PMID: 33552909). It has also been reported in ClinVar (Variation ID 552212) and it has been identified in 2/67960 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg186Trp) has been identified in individuals with methylmalonic acidemia and is classified as pathogenic by several clinical laboratories in ClinVar and they occur in one of highly conserved residus, which are thought to be involved in the formation of the active site where many pathogenic variants in this gene have been identified (Lerner-Ellis 2006 PMID: 16410054). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal autosomal methylmalonic acidemia. ACMG/AMP criteria provided: PM2_Supporting, PP3, PM5, PM3, PM1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.8

H;.

PhyloP100

5.7

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.98

Loss of MoRF binding (P = 0.0176);.;

MVP

1.0

MPC

0.90

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.97

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over