rs11067233

Variant names:

• chr12-109556403-C-G
• rs11067233
• NM_052845.4:c.*625G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052845.4(MMAB):​c.*625G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 453,852 control chromosomes in the GnomAD database, including 14,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4575 hom., cov: 31)
  • Exomes 𝑓: 0.25 (9667 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.817

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-109556403-C-G is Benign according to our data. Variant chr12-109556403-C-G is described in ClinVar as [Benign]. Clinvar id is 307053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*625G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712	c.*625G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36684 AN: 151930 Hom.: 4570 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.0911

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.225 AC: 29420 AN: 130496 Hom.: 3647 AF XY: 0.228 AC XY: 16273 AN XY: 71224

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.0885

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.246 AC: 74258 AN: 301804 Hom.: 9667 Cov.: 0 AF XY: 0.247 AC XY: 42551 AN XY: 172002

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.0872

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.248

GnomAD4 genome AF: 0.241 AC: 36710 AN: 152048 Hom.: 4575 Cov.: 31 AF XY: 0.240 AC XY: 17848 AN XY: 74310

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.0913

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.260

Alfa AF: 0.276 Hom.: 1166

Bravo AF: 0.234

Asia WGS AF: 0.165 AC: 575 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11067233; hg19: chr12-109994208;