Variant 12-109561046-TCGGCCCGGCGGCACA-TCGGCCCGGCGGCACACGGCCCGGCGGCACA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_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. Variant has been reported in ClinVar as Likely pathogenic (★★).

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:7

Conservation

PhyloP100: 5.67

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:

MMAB (HGNC:):

MMAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 203822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAB	NM_052845.4 linkuse as main transcript	c.563_577dupTGTGCCGCCGGGCCG	p.Val188_Ala192dup	conservative_inframe_insertion	7/9	ENST00000545712.7	NP_443077.1	Q96EY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7 linkuse as main transcript	c.563_577dupTGTGCCGCCGGGCCG	p.Val188_Ala192dup	conservative_inframe_insertion	7/9	1	NM_052845.4	ENSP00000445920.1		Q96EY8

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

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248548

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134930

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000592

Gnomad4 OTH exome

AF:

0.0000398

GnomAD4 genome

AF:

0.00000701

AC:

AN:

142732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69060

show subpopulations

Gnomad4 AFR

AF:

0.0000256

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This variant, c.563_577dup, results in the insertion of 5 amino acid(s) of the MMAB protein (p.Val188_Ala192dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs747499304, gnomAD 0.002%). This variant has been observed in individual(s) with clinical features of cobalamin B type methylmalonic aciduria (PMID: 16410054, 22695176; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203822). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 17, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Baumgartner lab, University Children's Hospital Zurich	Jun 01, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2014

The c.563_577dupTGTGCCGCCGGGCCG, the normal sequence with the bases that are duplicated in braces is: GCCG{TGTGCCGCCGGGCCG}AGAGAC. mutation in the MMAB gene has been reported previously in association with vitamin-B12 responsive methylmalonic acidemia (MMA) in a patient who presented with symptoms at day 7 of life (Lerner-Ellis et al., 2006). Mutation occurs in the active site of the MMAB enzyme (Lerner-Ellis et al., 2006). The c.563_577dupTGTGCCGCCGGGCCG mutation results in a insertion of 5 amino acids, denoted p.Val188_Ala192dup. The variant is found in MMAB panel(s). -

Methylmalonic acidemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 18, 2021

Variant summary: MMAB c.563_577dup15 (p.Val188_Ala192dup) results in an in-frame duplication that is predicted to duplicate 5 amino acids in the Cobalamin adenosyltransferase-like domain (IPR016030) of the encoded protein. The variant allele was found at a frequency of 8e-06 in 248548 control chromosomes. c.563_577dup15 has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Methylmalonic Acidemia (example, Lerner-Ellis_2006, Vatanavicharn_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over