12-109554344-C-G

Variant names:

• chr12-109554344-C-G
• rs35145546
• NM_052845.4:c.*2684G>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.*2684G>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 0.164 in 453,970 control chromosomes in the GnomAD database, including 6,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2209 hom., cov: 32)
  • Exomes 𝑓: 0.16 (4194 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290
• Publications: 12 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=-0.83).
• BP6: Variant 12-109554344-C-G is Benign according to our data. Variant chr12-109554344-C-G is described in ClinVar as [Benign]. Clinvar id is 307010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*2684G>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.*2684G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25537 AN: 152048 Hom.: 2213 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0990

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.162 AC: 21106 AN: 130492 AF XY: 0.162

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.163 AC: 49051 AN: 301804 Hom.: 4194 Cov.: 0 AF XY: 0.160 AC XY: 27504 AN XY: 172000

African (AFR) AF: 0.180 AC: 1538 AN: 8554

American (AMR) AF: 0.147 AC: 4000 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2030 AN: 10786

East Asian (EAS) AF: 0.147 AC: 1354 AN: 9210

South Asian (SAS) AF: 0.137 AC: 8186 AN: 59650

European-Finnish (FIN) AF: 0.112 AC: 1391 AN: 12368

Middle Eastern (MID) AF: 0.196 AC: 225 AN: 1150

European-Non Finnish (NFE) AF: 0.176 AC: 27970 AN: 158766

Other (OTH) AF: 0.168 AC: 2357 AN: 14046

GnomAD4 genome AF: 0.168 AC: 25545 AN: 152166 Hom.: 2209 Cov.: 32 AF XY: 0.163 AC XY: 12096 AN XY: 74416

African (AFR) AF: 0.184 AC: 7637 AN: 41492

American (AMR) AF: 0.156 AC: 2380 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3472

East Asian (EAS) AF: 0.139 AC: 718 AN: 5172

South Asian (SAS) AF: 0.129 AC: 624 AN: 4826

European-Finnish (FIN) AF: 0.0990 AC: 1050 AN: 10608

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11856 AN: 67988

Other (OTH) AF: 0.174 AC: 368 AN: 2114

Alfa AF: 0.175 Hom.: 430

Bravo AF: 0.175

Asia WGS AF: 0.149 AC: 518 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	-0.83
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-0.029
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: rs35145546; hg19: chr12-109992149;