12-109555798-C-A

Variant names:

• chr12-109555798-C-A
• rs11067231
• NM_052845.4:c.*1230G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 26 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 -20 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 VariationId is 307039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*1230G>T		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	ENST00000545712.7	c.*1230G>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

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

GnomAD2 exomes AF: 0.491 AC: 64022 AN: 130508 AF XY: 0.487

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 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

African (AFR) AF: 0.729 AC: 6237 AN: 8554

American (AMR) AF: 0.465 AC: 12687 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 5970 AN: 10786

East Asian (EAS) AF: 0.301 AC: 2776 AN: 9210

South Asian (SAS) AF: 0.423 AC: 25232 AN: 59648

European-Finnish (FIN) AF: 0.470 AC: 5810 AN: 12368

Middle Eastern (MID) AF: 0.601 AC: 691 AN: 1150

European-Non Finnish (NFE) AF: 0.540 AC: 85716 AN: 158754

Other (OTH) AF: 0.516 AC: 7249 AN: 14040

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

African (AFR) AF: 0.724 AC: 29976 AN: 41420

American (AMR) AF: 0.503 AC: 7666 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1846 AN: 3464

East Asian (EAS) AF: 0.297 AC: 1528 AN: 5140

South Asian (SAS) AF: 0.389 AC: 1869 AN: 4808

European-Finnish (FIN) AF: 0.463 AC: 4872 AN: 10522

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36396 AN: 67906

Other (OTH) AF: 0.581 AC: 1223 AN: 2106

Alfa AF: 0.554 Hom.: 66934

Bravo AF: 0.580

Asia WGS AF: 0.385 AC: 1337 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	-0.89
CADD	Benign	0.086
DANN	Benign	0.48
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11067231; hg19: chr12-109993603; COSMIC: COSV108027807; COSMIC: COSV108027807;