12-109554193-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.523

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
MMAB	NM_052845.4	c.*2835T>C		3_prime_UTR_variant	9/9	ENST00000545712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMAB	ENST00000545712.7	c.*2835T>C		3_prime_UTR_variant	9/9	1	NM_052845.4	P1

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

GnomAD3 exomes AF: 0.162 AC: 21111 AN: 130236 Hom.: 1767 AF XY: 0.162 AC XY: 11539 AN XY: 71122

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 SAS exome AF: 0.141

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

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.168

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

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0989

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.175

Alfa AF: 0.177 Hom.: 736

Bravo AF: 0.176

Asia WGS AF: 0.153 AC: 531 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.7
Dann	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs12817689; hg19: chr12-109991998;