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 Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 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 acidemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• methylmalonic aciduria, cblB type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 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, 11 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/Likely_pathogenic. ClinVar VariationId is 1017834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052845.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	NM_052845.4	MANE Select	c.563_577delTGTGCCGCCGGGCCG	p.Val188_Ala192del	disruptive_inframe_deletion	Exon 7 of 9	NP_443077.1	Q96EY8
	MMAB	NR_038118.2		n.674_688delTGTGCCGCCGGGCCG		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMAB	ENST00000545712.7	TSL:1 MANE Select	c.563_577delTGTGCCGCCGGGCCG	p.Val188_Ala192del	disruptive_inframe_deletion	Exon 7 of 9	ENSP00000445920.1	Q96EY8
	MMAB	ENST00000878519.1		c.626_640delTGTGCCGCCGGGCCG	p.Val209_Ala213del	disruptive_inframe_deletion	Exon 8 of 10	ENSP00000548578.1
	MMAB	ENST00000878520.1		c.563_577delTGTGCCGCCGGGCCG	p.Val188_Ala192del	disruptive_inframe_deletion	Exon 7 of 8	ENSP00000548579.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Methylmalonic aciduria, cblB type (3)

Computational scores

Source: dbNSFP v4.9

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;