12-109553880-C-T

Variant names:

• chr12-109553880-C-T
• rs11067227
• NM_052845.4:c.*3148G>A

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.*3148G>A 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 453,906 control chromosomes in the GnomAD database, including 14,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4576 hom., cov: 33)
  • Exomes 𝑓: 0.25 (9671 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.471
• Publications: 14 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 12-109553880-C-T is Benign according to our data. Variant chr12-109553880-C-T is described in ClinVar as [Benign]. Clinvar id is 307003.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.*3148G>A		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.*3148G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36722 AN: 151996 Hom.: 4571 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.226 AC: 29428 AN: 130484 AF XY: 0.229

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.0882

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.246 AC: 74272 AN: 301792 Hom.: 9671 Cov.: 0 AF XY: 0.247 AC XY: 42559 AN XY: 171992

African (AFR) AF: 0.227 AC: 1944 AN: 8554

American (AMR) AF: 0.175 AC: 4774 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 3138 AN: 10786

East Asian (EAS) AF: 0.0869 AC: 800 AN: 9210

South Asian (SAS) AF: 0.228 AC: 13579 AN: 59650

European-Finnish (FIN) AF: 0.283 AC: 3505 AN: 12368

Middle Eastern (MID) AF: 0.290 AC: 333 AN: 1150

European-Non Finnish (NFE) AF: 0.269 AC: 42715 AN: 158762

Other (OTH) AF: 0.248 AC: 3484 AN: 14038

GnomAD4 genome AF: 0.242 AC: 36748 AN: 152114 Hom.: 4576 Cov.: 33 AF XY: 0.240 AC XY: 17867 AN XY: 74360

African (AFR) AF: 0.221 AC: 9186 AN: 41480

American (AMR) AF: 0.205 AC: 3127 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 957 AN: 3472

East Asian (EAS) AF: 0.0912 AC: 473 AN: 5188

South Asian (SAS) AF: 0.212 AC: 1020 AN: 4818

European-Finnish (FIN) AF: 0.286 AC: 3023 AN: 10568

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18099 AN: 67994

Other (OTH) AF: 0.260 AC: 550 AN: 2112

Alfa AF: 0.256 Hom.: 2736

Bravo AF: 0.234

Asia WGS AF: 0.165 AC: 573 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 13, 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	0.57
DANN	Benign	0.84
PhyloP100		-0.47
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: rs11067227; hg19: chr12-109991685;