Genetic Variant MMAB:p.Met239Arg (chr12-109557065-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_052845.4(MMAB):c.716T>G(p.Met239Arg) 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. 17/22 in silico tools predict 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. M239K) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MMAB
NM_052845.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0210

Publications

62 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a chain Corrinoid adenosyltransferase MMAB (size 217) in uniprot entity MMAB_HUMAN there are 29 pathogenic changes around while only 7 benign (81%) in NM_052845.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05167088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4 link	c.716T>G	p.Met239Arg	missense_variant	Exon 9 of 9	ENST00000545712.7	NP_443077.1	Q96EY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7 link	c.716T>G	p.Met239Arg	missense_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1		Q96EY8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726944

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111332

Other (OTH)

AF:

0.00

AC:

AN:

60364

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.080

T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-1.7

N;.

PhyloP100

-0.021

PrimateAI

Benign

0.31

PROVEAN

Benign

1.9

N;.

REVEL

Benign

0.19

Sift

Benign

0.50

T;.

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;.

Vest4

0.056

MutPred

0.23

Gain of methylation at K240 (P = 0.0267);.;

MVP

0.56

MPC

0.34

ClinPred

0.058

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.26

gMVP

0.41

Mutation Taster

=96/4

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over