rs2241201

Positions:

• chr12-109554327-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_052845.4(MMAB):​c.*2701G>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 0.281 in 453,820 control chromosomes in the GnomAD database, including 19,874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (9024 hom., cov: 32)
  • Exomes 𝑓: 0.26 (10850 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.413

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-109554327-C-G is Benign according to our data. Variant chr12-109554327-C-G is described in ClinVar as [Benign]. Clinvar id is 307009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMAB	NM_052845.4	c.*2701G>C		3_prime_UTR_variant	9/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.*2701G>C		3_prime_UTR_variant	9/9	1	NM_052845.4	P1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49326 AN: 151910 Hom.: 8996 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.265 AC: 34608 AN: 130478 Hom.: 4952 AF XY: 0.259 AC XY: 18411 AN XY: 71222

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.259 AC: 78154 AN: 301792 Hom.: 10850 Cov.: 0 AF XY: 0.251 AC XY: 43126 AN XY: 171992

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.214

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.325 AC: 49406 AN: 152028 Hom.: 9024 Cov.: 32 AF XY: 0.316 AC XY: 23514 AN XY: 74336

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.319

Alfa AF: 0.292 Hom.: 1302

Bravo AF: 0.346

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.33

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: rs2241201; hg19: chr12-109992132;