rs11067231

chr12-109555798-C-Achr12-109555798-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.*1230G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 453,606 control chromosomes in the GnomAD database, including 65,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25399 hom., cov: 30)
  • Exomes 𝑓: 0.50 (39635 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

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=-0.89).
• BP6: Variant 12-109555798-C-A is Benign according to our data. Variant chr12-109555798-C-A is described in ClinVar as [Benign]. Clinvar id is 307039.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
MMAB	NM_052845.4	c.*1230G>T		3_prime_UTR_variant	9/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.*1230G>T		3_prime_UTR_variant	9/9	1	NM_052845.4	P1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 85968 AN: 151704 Hom.: 25355 Cov.: 30

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.580

GnomAD3 exomes AF: 0.491 AC: 64022 AN: 130508 Hom.: 16399 AF XY: 0.487 AC XY: 34685 AN XY: 71230

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.420

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.505 AC: 152368 AN: 301784 Hom.: 39635 Cov.: 0 AF XY: 0.498 AC XY: 85657 AN XY: 171986

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.465

Gnomad4 ASJ exome AF: 0.553

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.423

Gnomad4 FIN exome AF: 0.470

Gnomad4 NFE exome AF: 0.540

Gnomad4 OTH exome AF: 0.516

GnomAD4 genome AF: 0.567 AC: 86074 AN: 151822 Hom.: 25399 Cov.: 30 AF XY: 0.557 AC XY: 41328 AN XY: 74222

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.581

Alfa AF: 0.545 Hom.: 39534

Bravo AF: 0.580

Asia WGS AF: 0.385 AC: 1337 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	-0.89
Cadd	Benign	0.086
Dann	Benign	0.48

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: rs11067231; hg19: chr12-109993603;