rs2241201

Variant names:

• chr12-109554327-C-G
• rs2241201
• NM_052845.4:c.*2701G>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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.413
• Publications: 16 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=-0.9).
• 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*2701G>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.*2701G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

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

GnomAD2 exomes AF: 0.265 AC: 34608 AN: 130478 AF XY: 0.259

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 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

African (AFR) AF: 0.502 AC: 4293 AN: 8554

American (AMR) AF: 0.290 AC: 7915 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 2833 AN: 10786

East Asian (EAS) AF: 0.214 AC: 1973 AN: 9210

South Asian (SAS) AF: 0.196 AC: 11677 AN: 59650

European-Finnish (FIN) AF: 0.186 AC: 2302 AN: 12364

Middle Eastern (MID) AF: 0.314 AC: 361 AN: 1150

European-Non Finnish (NFE) AF: 0.271 AC: 43028 AN: 158760

Other (OTH) AF: 0.269 AC: 3772 AN: 14044

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

African (AFR) AF: 0.502 AC: 20777 AN: 41428

American (AMR) AF: 0.298 AC: 4552 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5164

South Asian (SAS) AF: 0.177 AC: 854 AN: 4824

European-Finnish (FIN) AF: 0.178 AC: 1882 AN: 10592

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18328 AN: 67960

Other (OTH) AF: 0.319 AC: 673 AN: 2108

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: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	-0.90
CADD	Benign	1.5
DANN	Benign	0.33
PhyloP100		-0.41
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: rs2241201; hg19: chr12-109992132;