12-109562388-C-T

Variant names:

• chr12-109562388-C-T
• rs7134594
• NM_052845.4:c.349-536G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052845.4(MMAB):​c.349-536G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 152,126 control chromosomes in the GnomAD database, including 25,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25478 hom., cov: 33)
• Consequence: MMAB NM_052845.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.84
• Publications: 104 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.349-536G>A		intron_variant	Intron 4 of 8	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.349-536G>A		intron_variant	Intron 4 of 8	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86140 AN: 152008 Hom.: 25434 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.581

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.567 AC: 86246 AN: 152126 Hom.: 25478 Cov.: 33 AF XY: 0.557 AC XY: 41419 AN XY: 74370

African (AFR) AF: 0.724 AC: 30050 AN: 41486

American (AMR) AF: 0.501 AC: 7672 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3472

East Asian (EAS) AF: 0.297 AC: 1537 AN: 5178

South Asian (SAS) AF: 0.389 AC: 1878 AN: 4826

European-Finnish (FIN) AF: 0.464 AC: 4900 AN: 10564

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36438 AN: 67984

Other (OTH) AF: 0.581 AC: 1228 AN: 2112

Alfa AF: 0.548 Hom.: 86170

Bravo AF: 0.581

Asia WGS AF: 0.383 AC: 1332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.15
DANN	Benign	0.63
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs7134594; hg19: chr12-110000193;