chr12-109573424-G-T

Position:

• chr12-109573424-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052845.4(MMAB):​c.57C>A​(p.Arg19Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,607,664 control chromosomes in the GnomAD database, including 60,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7459 hom., cov: 33)
  • Exomes 𝑓: 0.27 (53341 hom.)
• Consequence: MMAB NM_052845.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0470

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]

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-109573424-G-T is Benign according to our data. Variant chr12-109573424-G-T is described in ClinVar as [Benign]. Clinvar id is 262247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109573424-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.047 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMAB	NM_052845.4	c.57C>A	p.Arg19Arg	synonymous_variant	1/9	ENST00000545712.7	NP_443077.1
MVK	XM_047428873.1	c.139G>T	p.Ala47Ser	missense_variant	1/11		XP_047284829.1
MVK	XM_017019313.3	c.-162G>T		5_prime_UTR_variant	1/10		XP_016874802.1
MMAB	NR_038118.2	n.81C>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.57C>A	p.Arg19Arg	synonymous_variant	1/9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46640 AN: 151714 Hom.: 7423 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.269 AC: 63010 AN: 234304 Hom.: 8743 AF XY: 0.266 AC XY: 34148 AN XY: 128616

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.266 AC: 387968 AN: 1455832 Hom.: 53341 Cov.: 35 AF XY: 0.267 AC XY: 193153 AN XY: 724124

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.308 AC: 46726 AN: 151832 Hom.: 7459 Cov.: 33 AF XY: 0.306 AC XY: 22691 AN XY: 74202

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.314

Alfa AF: 0.266 Hom.: 2788

Bravo AF: 0.314

Asia WGS AF: 0.184 AC: 640 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mevalonic aciduria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Methylmalonic acidemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hyperimmunoglobulin D with periodic fever Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.9
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10774774; hg19: chr12-110011229; COSMIC: COSV57169501; COSMIC: COSV57169501;