chr12-109561046-TCGGCCCGGCGGCACA-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 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. Variant has been reported in ClinVar as Pathogenic (★).

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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-TCGGCCCGGCGGCACA-T is Pathogenic according to our data. Variant chr12-109561046-TCGGCCCGGCGGCACA-T is described in ClinVar as [Pathogenic]. Clinvar id 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000376

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.87e-7

Gnomad4 OTH exome AF: 0.0000199

GnomAD4 genome Cov.: 30

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 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. -

Jul 06, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555274496; hg19: chr12-109998851;