chr12-109557065-A-T

Variant names:

• chr12-109557065-A-T
• rs9593
• NM_052845.4:c.716T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0210
• Publications: 62 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 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
• 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 VariationId is 96245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.716T>A	p.Met239Lys	missense_variant	Exon 9 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.716T>A	p.Met239Lys	missense_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86158 AN: 151984 Hom.: 25430 Cov.: 33

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

GnomAD2 exomes AF: 0.502 AC: 126142 AN: 251412 AF XY: 0.498

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 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.: 35 AF XY: 0.515 AC XY: 373969 AN XY: 726228

African (AFR) AF: 0.729 AC: 24384 AN: 33444

American (AMR) AF: 0.471 AC: 21056 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 14388 AN: 26126

East Asian (EAS) AF: 0.299 AC: 11869 AN: 39698

South Asian (SAS) AF: 0.417 AC: 35962 AN: 86226

European-Finnish (FIN) AF: 0.470 AC: 25063 AN: 53364

Middle Eastern (MID) AF: 0.584 AC: 3360 AN: 5752

European-Non Finnish (NFE) AF: 0.529 AC: 587523 AN: 1109958

Other (OTH) AF: 0.519 AC: 31283 AN: 60316

GnomAD4 genome AF: 0.567 AC: 86264 AN: 152102 Hom.: 25474 Cov.: 33 AF XY: 0.557 AC XY: 41435 AN XY: 74370

African (AFR) AF: 0.724 AC: 30046 AN: 41496

American (AMR) AF: 0.503 AC: 7687 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1541 AN: 5172

South Asian (SAS) AF: 0.390 AC: 1882 AN: 4830

European-Finnish (FIN) AF: 0.464 AC: 4913 AN: 10590

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36418 AN: 67942

Other (OTH) AF: 0.581 AC: 1227 AN: 2112

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

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:6

Jul 22, 2021

Genome-Nilou Lab

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

- -

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. -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.55
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.040	T;T
MetaRNN	Benign	0.0000012	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.1	N;.
PhyloP100		-0.021
PrimateAI	Benign	0.32	T
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	T
GERP RS		1.4
Varity_R		0.23
gMVP		0.46
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9593; hg19: chr12-109994870; COSMIC: COSV57169652; COSMIC: COSV57169652;