rs9593

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 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

Scores

Clinical Significance

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

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

MMAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.716T>A	p.Met239Lys	missense	Exon 9 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.827T>A		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.716T>A	p.Met239Lys	missense	Exon 9 of 9	ENSP00000445920.1	Q96EY8
MMAB	ENST00000878519.1		c.779T>A	p.Met260Lys	missense	Exon 10 of 10	ENSP00000548578.1
MMAB	ENST00000878520.1		c.656T>A	p.Met219Lys	missense	Exon 8 of 8	ENSP00000548579.1

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

GnomAD2 exomes

AF:

0.502

AC:

126142

AN:

251412

AF XY:

0.498

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19103

38206

57310

76413

95516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16602

33204

49806

66408

83010

<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:

0.567

AC:

86264

AN:

152102

Hom.:

25474

Cov.:

AF XY:

0.557

AC XY:

41435

AN XY:

74370

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1869

3737

5606

7474

9343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblB type (6)

not specified (5)

not provided (2)

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.13

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.040

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.1

PhyloP100

-0.021

PrimateAI

Benign

0.32

PROVEAN

Benign

2.2

REVEL

Benign

0.21

Sift

Benign

1.0

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.071

MPC

0.34

ClinPred

0.0042

GERP RS

1.4

Varity_R

0.23

gMVP

0.46

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over