chr12-109554193-A-G

Variant names:

• chr12-109554193-A-G
• rs12817689
• NM_052845.4:c.*2835T>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.*2835T>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 0.165 in 453,124 control chromosomes in the GnomAD database, including 6,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2260 hom., cov: 32)
  • Exomes 𝑓: 0.16 (4199 hom.)
• Consequence: MMAB NM_052845.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.523
• 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=-0.9).
• BP6: Variant 12-109554193-A-G is Benign according to our data. Variant chr12-109554193-A-G is described in ClinVar as [Benign]. Clinvar id is 307007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.*2835T>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.*2835T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25771 AN: 152010 Hom.: 2263 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0989

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.162 AC: 21111 AN: 130236 AF XY: 0.162

Gnomad AFR exome AF: 0.185

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: 0.181

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.163 AC: 49028 AN: 300996 Hom.: 4199 Cov.: 0 AF XY: 0.160 AC XY: 27454 AN XY: 171388

African (AFR) AF: 0.184 AC: 1574 AN: 8536

American (AMR) AF: 0.147 AC: 4007 AN: 27266

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2028 AN: 10768

East Asian (EAS) AF: 0.147 AC: 1356 AN: 9196

South Asian (SAS) AF: 0.138 AC: 8223 AN: 59638

European-Finnish (FIN) AF: 0.112 AC: 1389 AN: 12364

Middle Eastern (MID) AF: 0.194 AC: 223 AN: 1148

European-Non Finnish (NFE) AF: 0.176 AC: 27873 AN: 158076

Other (OTH) AF: 0.168 AC: 2355 AN: 14004

GnomAD4 genome AF: 0.169 AC: 25781 AN: 152128 Hom.: 2260 Cov.: 32 AF XY: 0.164 AC XY: 12203 AN XY: 74362

African (AFR) AF: 0.189 AC: 7835 AN: 41490

American (AMR) AF: 0.156 AC: 2384 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3466

East Asian (EAS) AF: 0.140 AC: 723 AN: 5168

South Asian (SAS) AF: 0.130 AC: 627 AN: 4826

European-Finnish (FIN) AF: 0.0989 AC: 1049 AN: 10602

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

European-Non Finnish (NFE) AF: 0.175 AC: 11887 AN: 67994

Other (OTH) AF: 0.175 AC: 369 AN: 2106

Alfa AF: 0.177 Hom.: 744

Bravo AF: 0.176

Asia WGS AF: 0.153 AC: 531 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	1.7
DANN	Benign	0.62
PhyloP100		0.52
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: rs12817689; hg19: chr12-109991998;