rs1555274496

chr12-109561046-TCGGCCCGGCGGCACA-Tchr12-109561046-TCGGCCCGGCGGCACA-TCGGCCCGGCGGCACACGGCCCGGCGGCACA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_052845.4(MMAB):c.563_577del(p.Val188_Ala192del) variant causes a 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 (★). 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 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 8 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_052845.4
• 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/exons	MANE	UniProt
MMAB	NM_052845.4	c.563_577del	p.Val188_Ala192del	inframe_deletion	7/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.563_577del	p.Val188_Ala192del	inframe_deletion	7/9	1	NM_052845.4	P1

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

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	ClinVar contains an entry for this variant (Variation ID: 1017834). 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MMAB-related conditions. 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. -

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;