rs763935916

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_052845.4(MMAB):c.197-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000217 in 1,612,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MMAB
NM_052845.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.94

Publications

5 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.5, offset of 10, new splice context is: ttttccacatggttttctAGtac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 12-109568864-C-A is Pathogenic according to our data. Variant chr12-109568864-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 219008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4 link	c.197-1G>T	splice_acceptor_variant, intron_variant	Intron 2 of 8	ENST00000545712.7	NP_443077.1	Q96EY8
MMAB	NR_038118.2 link	n.221-1G>T	splice_acceptor_variant, intron_variant	Intron 2 of 9
MMAB	XM_011538267.4 link	c.-451G>T	upstream_gene_variant			XP_011536569.1
MMAB	XM_011538269.3 link	c.-596G>T	upstream_gene_variant			XP_011536571.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7 link	c.197-1G>T		splice_acceptor_variant, intron_variant	Intron 2 of 8	1	NM_052845.4	ENSP00000445920.1		Q96EY8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151900

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251468

AF XY:

0.0000662

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460308

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000313

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110576

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151900

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000436

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Pathogenic:9Other:1

Nov 15, 2021

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant disease (PMID: 12471062, 24516753, 30022420, 26589311). Functional assessments of this variant are not available in the literature. c.197-1G>T has been observed in population frequency databases (gnomAD: SAS 0.03%). In summary, NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jun 01, 2021

Baumgartner lab, University Children's Hospital Zurich

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). This variant is present in population databases (rs763935916, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 19, 2020

Shieh Lab, University of California, San Francisco

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster. -

Methylmalonic acidemia

Pathogenic:2

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic aciduria cobalamin B type (Lerner-Ellis 2006 PMID: 16410054, Dobson 2002 PMID: 12471062, Al-Shamsi 2014 PMID: 24516753, Shafaat 2018 PMID: 30022420, Al-Jasmi 2016 PMID: 26589311). It has also been reported in ClinVar (Variation ID 219008). It has also been identified in 1/67974 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MMAB gene is an established disease mechanism in autosomal recessive methylmalonic aciduria cobalamin B type. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic aciduria cobalamin B type. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_Strong. -

Jul 08, 2016

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic. -

Methylmalonic aciduria

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1, PS3,PM3 (modertae),PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.9

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.61

Position offset: -11

DS_AL_spliceai

0.80

Position offset: -1

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

Publications

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rs763935916

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over