Genetic Variant MMAB:c.349-3dupC (chr12-109561854-T-TG) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_052845.4(MMAB):c.349-3dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,602,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MMAB
NM_052845.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.96

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 12-109561854-T-TG is Benign according to our data. Variant chr12-109561854-T-TG is described in ClinVar as Benign. ClinVar VariationId is 466215.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.349-3dupC		splice_region intron	N/A	NP_443077.1
	MMAB	NR_038118.2		n.373-3dupC		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.349-3_349-2insC	splice_region intron	N/A	ENSP00000445920.1
MMAB	ENST00000540016.5	TSL:3	c.193-3_193-2insC	splice_region intron	N/A	ENSP00000474582.1
MMAB	ENST00000420167.6	TSL:4	n.178-3_178-2insC	splice_region intron	N/A	ENSP00000416136.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000392

AC:

AN:

229522

AF XY:

0.0000563

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000569

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000590

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1450732

Hom.:

Cov.:

AF XY:

0.0000264

AC XY:

AN XY:

720658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33276

American (AMR)

AF:

0.0000229

AC:

AN:

43748

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39360

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84552

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52256

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

1105936

Other (OTH)

AF:

0.0000334

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Benign:1

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MMAB-related disorder

Benign:1

Sep 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

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

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

12-109561854-TG-TGG

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over