rs1555274496

Variant names:

• chr12-109561046-TCGGCCCGGCGGCACA-T
• rs1555274496
• NM_052845.4:c.563_577delTGTGCCGCCGGGCCG

Your query was ambiguous. Multiple possible variants found:

• chr12-109561046-TCGGCCCGGCGGCACA-T
• chr12-109561046-TCGGCCCGGCGGCACA-TCGGCCCGGCGGCACACGGCCCGGCGGCACA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_052845.4(MMAB):​c.563_577delTGTGCCGCCGGGCCG​(p.Val188_Ala192del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000229 in 1,307,584 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V188V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: MMAB NM_052845.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.15
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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-TCGGCCCGGCGGCACA-T is Pathogenic according to our data. Variant chr12-109561046-TCGGCCCGGCGGCACA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1017834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.563_577delTGTGCCGCCGGGCCG	p.Val188_Ala192del	disruptive_inframe_deletion	Exon 7 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.563_577delTGTGCCGCCGGGCCG	p.Val188_Ala192del	disruptive_inframe_deletion	Exon 7 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1307584 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 648758

African (AFR) AF: 0.00 AC: 0 AN: 28962

American (AMR) AF: 0.00 AC: 0 AN: 40022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20384

East Asian (EAS) AF: 0.0000376 AC: 1 AN: 26606

South Asian (SAS) AF: 0.00 AC: 0 AN: 84918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4960

European-Non Finnish (NFE) AF: 9.87e-7 AC: 1 AN: 1013376

Other (OTH) AF: 0.0000199 AC: 1 AN: 50282

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblB type Pathogenic:1 Uncertain:1

Jul 06, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with MMAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017834). This variant disrupts a region of the MMAB protein in which other variant(s) (p.Arg191Trp) have been determined to be pathogenic (PMID: 20556797, 23707710, 27591164, 30022420). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This variant, c.563_577del, results in the deletion of 5 amino acid(s) of the MMAB protein (p.Val188_Ala192del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

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

Other links and lift over

dbSNP: rs1555274496; hg19: chr12-109998851;