12-109573424-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_052845.4(MMAB):c.57C>A(p.Arg19Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,607,664 control chromosomes in the GnomAD database, including 60,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R19R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 7459 hom., cov: 33)

Exomes 𝑓: 0.27 ( 53341 hom. )

Consequence

MMAB
NM_052845.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0470

Publications

16 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 links:

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK Gene-Disease associations (from GenCC):

porokeratosis 3, disseminated superficial actinic type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hyperimmunoglobulinemia D with periodic fever
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
mevalonate kinase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mevalonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
disseminated superficial actinic porokeratosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
porokeratosis of Mibelli
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 12-109573424-G-T is Benign according to our data. Variant chr12-109573424-G-T is described in ClinVar as Benign. ClinVar VariationId is 262247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.047 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 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.57C>A	p.Arg19Arg	synonymous	Exon 1 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.81C>A		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.57C>A	p.Arg19Arg	synonymous	Exon 1 of 9	ENSP00000445920.1	Q96EY8
MMAB	ENST00000878519.1		c.57C>A	p.Arg19Arg	synonymous	Exon 1 of 10	ENSP00000548578.1
MMAB	ENST00000878520.1		c.57C>A	p.Arg19Arg	synonymous	Exon 1 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46640

AN:

151714

Hom.:

7423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.133

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.295

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.317

GnomAD2 exomes

AF:

0.269

AC:

63010

AN:

234304

AF XY:

0.266

show subpopulations

Gnomad AFR exome

AF:

0.415

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.297

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.266

AC:

387968

AN:

1455832

Hom.:

53341

Cov.:

AF XY:

0.267

AC XY:

193153

AN XY:

724124

show subpopulations

African (AFR)

AF:

0.412

AC:

13740

AN:

33388

American (AMR)

AF:

0.283

AC:

12491

AN:

44124

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7607

AN:

26046

East Asian (EAS)

AF:

0.119

AC:

4711

AN:

39534

South Asian (SAS)

AF:

0.230

AC:

19713

AN:

85844

European-Finnish (FIN)

AF:

0.297

AC:

15111

AN:

50916

Middle Eastern (MID)

AF:

0.294

AC:

1627

AN:

5532

European-Non Finnish (NFE)

AF:

0.267

AC:

296683

AN:

1110334

Other (OTH)

AF:

0.271

AC:

16285

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

16795

33589

50384

67178

83973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9782

19564

29346

39128

48910

<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:

0.308

AC:

46726

AN:

151832

Hom.:

7459

Cov.:

AF XY:

0.306

AC XY:

22691

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.401

AC:

16569

AN:

41352

American (AMR)

AF:

0.294

AC:

4494

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

974

AN:

3468

East Asian (EAS)

AF:

0.133

AC:

683

AN:

5132

South Asian (SAS)

AF:

0.217

AC:

1049

AN:

4826

European-Finnish (FIN)

AF:

0.295

AC:

3119

AN:

10556

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18863

AN:

67908

Other (OTH)

AF:

0.314

AC:

663

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1659

3319

4978

6638

8297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.271

Hom.:

3342

Bravo

AF:

0.314

Asia WGS

AF:

0.184

AC:

640

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblB type (4)

not specified (4)

not provided (3)

Hyperimmunoglobulin D with periodic fever (1)

Methylmalonic acidemia (1)

Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.9

(source)

DANN

Benign

0.85

PhyloP100

-0.047

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=300/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over