12-109561046-TCGGCCCGGCGGCACA-TCGGCCCGGCGGCACACGGCCCGGCGGCACA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM4PP5_Very_Strong

The NM_052845.4(MMAB):c.563_577dupTGTGCCGCCGGGCCG(p.Val188_Ala192dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.0000434 in 1,450,316 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E193E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

MMAB
NM_052845.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.67

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 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_052845.4

PM4

Nonframeshift variant in NON repetitive region in NM_052845.4.

PP5

Variant 12-109561046-T-TCGGCCCGGCGGCACA is Pathogenic according to our data. Variant chr12-109561046-T-TCGGCCCGGCGGCACA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.563_577dupTGTGCCGCCGGGCCG	p.Val188_Ala192dup	conservative_inframe_insertion	Exon 7 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.674_688dupTGTGCCGCCGGGCCG		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MMAB	ENST00000545712.7	TSL:1 MANE Select	c.563_577dupTGTGCCGCCGGGCCG	p.Val188_Ala192dup	conservative_inframe_insertion	Exon 7 of 9	ENSP00000445920.1	Q96EY8
MMAB	ENST00000878519.1		c.626_640dupTGTGCCGCCGGGCCG	p.Val209_Ala213dup	conservative_inframe_insertion	Exon 8 of 10	ENSP00000548578.1
MMAB	ENST00000878520.1		c.563_577dupTGTGCCGCCGGGCCG	p.Val188_Ala192dup	conservative_inframe_insertion	Exon 7 of 8	ENSP00000548579.1

Frequencies

GnomAD3 genomes

AF:

0.00000701

AC:

AN:

142732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000256

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248548

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1307584

Hom.:

Cov.:

AF XY:

0.0000432

AC XY:

AN XY:

648758

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28962

American (AMR)

AF:

0.00

AC:

AN:

40022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20384

East Asian (EAS)

AF:

0.00

AC:

AN:

26606

South Asian (SAS)

AF:

0.00

AC:

AN:

84918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4960

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

1013376

Other (OTH)

AF:

0.0000398

AC:

AN:

50282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00000701

AC:

AN:

142732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69060

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000256

AC:

AN:

39004

American (AMR)

AF:

0.00

AC:

AN:

14088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.00

AC:

AN:

4304

South Asian (SAS)

AF:

0.00

AC:

AN:

4098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65492

Other (OTH)

AF:

0.00

AC:

AN:

2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic aciduria, cblB type (6)

Methylmalonic acidemia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=35/65

disease causing (ClinVar)

(source)

Splicing

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