12-109557065-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_052845.4(MMAB):c.716T>A(p.Met239Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,611,698 control chromosomes in the GnomAD database, including 224,121 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25474 hom., cov: 33)

Exomes 𝑓: 0.52 ( 198647 hom. )

Consequence

MMAB
NM_052845.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0210

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1608169E-6).

BP6

Variant 12-109557065-A-T is Benign according to our data. Variant chr12-109557065-A-T is described in ClinVar as [Benign]. Clinvar id is 96245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109557065-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4 link	c.716T>A	p.Met239Lys	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>A	p.Met239Lys	missense_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1		Q96EY8

Frequencies

GnomAD3 genomes

AF:

0.567

AC:

86158

AN:

151984

Hom.:

25430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.724

Gnomad AMI

AF:

0.587

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.390

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.536

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.502

AC:

126142

AN:

251412

Hom.:

32890

AF XY:

0.498

AC XY:

67604

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.733

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.554

Gnomad EAS exome

AF:

0.296

Gnomad SAS exome

AF:

0.415

Gnomad FIN exome

AF:

0.467

Gnomad NFE exome

AF:

0.539

Gnomad OTH exome

AF:

0.512

GnomAD4 exome

AF:

0.517

AC:

754888

AN:

1459596

Hom.:

198647

Cov.:

AF XY:

0.515

AC XY:

373969

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.729

Gnomad4 AMR exome

AF:

0.471

Gnomad4 ASJ exome

AF:

0.551

Gnomad4 EAS exome

AF:

0.299

Gnomad4 SAS exome

AF:

0.417

Gnomad4 FIN exome

AF:

0.470

Gnomad4 NFE exome

AF:

0.529

Gnomad4 OTH exome

AF:

0.519

GnomAD4 genome

AF:

0.567

AC:

86264

AN:

152102

Hom.:

25474

Cov.:

AF XY:

0.557

AC XY:

41435

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.724

Gnomad4 AMR

AF:

0.503

Gnomad4 ASJ

AF:

0.534

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.390

Gnomad4 FIN

AF:

0.464

Gnomad4 NFE

AF:

0.536

Gnomad4 OTH

AF:

0.581

Alfa

AF:

0.554

Hom.:

7650

Bravo

AF:

0.581

TwinsUK

AF:

0.524

AC:

1944

ALSPAC

AF:

0.509

AC:

1963

ESP6500AA

AF:

0.721

AC:

3176

ESP6500EA

AF:

0.532

AC:

4579

ExAC

AF:

0.509

AC:

61841

Asia WGS

AF:

0.384

AC:

1335

AN:

3478

EpiCase

AF:

0.555

EpiControl

AF:

0.548

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Benign:6

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: 51% of total chromosomes in ExAC -

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MMAB c.716T>A (p.Met239Lys) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. This variant was found in 61824/121354 control chromosomes (16355 homozygotes) at a frequency of 0.5094517, which is approximately 365 times the estimated maximal expected allele frequency of a pathogenic MMAB variant (0.0013944); thus this variant is a benign common polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign. -

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.040

T;T

MetaRNN

Benign

0.0000012

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.1

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

2.2

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;.

Vest4

0.071

MPC

0.34

ClinPred

0.0042

GERP RS

1.4

Varity_R

0.23

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over