12-109556171-C-G

Variant names:

• chr12-109556171-C-G
• rs877710
• NM_052845.4:c.*857G>C

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.*857G>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 0.526 in 453,090 control chromosomes in the GnomAD database, including 65,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25473 hom., cov: 31)
  • Exomes 𝑓: 0.51 (39558 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.277
• Publications: 25 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=-0.86).
• BP6: Variant 12-109556171-C-G is Benign according to our data. Variant chr12-109556171-C-G is described in ClinVar as Benign. ClinVar VariationId is 307047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*857G>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	ENST00000545712.7	c.*857G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86129 AN: 151894 Hom.: 25429 Cov.: 31

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.581

GnomAD2 exomes AF: 0.491 AC: 64019 AN: 130412 AF XY: 0.487

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.505 AC: 152056 AN: 301078 Hom.: 39558 Cov.: 0 AF XY: 0.498 AC XY: 85415 AN XY: 171490

African (AFR) AF: 0.729 AC: 6237 AN: 8552

American (AMR) AF: 0.466 AC: 12690 AN: 27256

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 5966 AN: 10774

East Asian (EAS) AF: 0.302 AC: 2772 AN: 9192

South Asian (SAS) AF: 0.423 AC: 25245 AN: 59626

European-Finnish (FIN) AF: 0.470 AC: 5804 AN: 12358

Middle Eastern (MID) AF: 0.603 AC: 692 AN: 1148

European-Non Finnish (NFE) AF: 0.540 AC: 85406 AN: 158150

Other (OTH) AF: 0.517 AC: 7244 AN: 14022

GnomAD4 genome AF: 0.567 AC: 86235 AN: 152012 Hom.: 25473 Cov.: 31 AF XY: 0.557 AC XY: 41408 AN XY: 74296

African (AFR) AF: 0.724 AC: 30030 AN: 41456

American (AMR) AF: 0.503 AC: 7673 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1848 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1542 AN: 5170

South Asian (SAS) AF: 0.390 AC: 1878 AN: 4820

European-Finnish (FIN) AF: 0.464 AC: 4892 AN: 10542

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36449 AN: 67974

Other (OTH) AF: 0.582 AC: 1225 AN: 2106

Alfa AF: 0.493 Hom.: 2539

Bravo AF: 0.581

Asia WGS AF: 0.384 AC: 1336 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	-0.86
CADD	Benign	0.86
DANN	Benign	0.73
PhyloP100		-0.28
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: rs877710; hg19: chr12-109993976; COSMIC: COSV57171067; COSMIC: COSV57171067;