12-109573425-C-T

Position:

chr12-109573425-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000545712.7(MMAB):c.56G>A(p.Arg19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,607,798 control chromosomes in the GnomAD database, including 60,788 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.31 ( 7460 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53328 hom. )

Consequence

MMAB
ENST00000545712.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.26

Variant links:

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 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052776933).

BP6

Variant 12-109573425-C-T is Benign according to our data. Variant chr12-109573425-C-T is described in ClinVar as [Benign]. Clinvar id is 262246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109573425-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MMAB	NM_052845.4 linkuse as main transcript	c.56G>A	p.Arg19His	missense_variant	1/9	ENST00000545712.7	NP_443077.1
MVK	XM_047428873.1 linkuse as main transcript	c.140C>T	p.Ala47Val	missense_variant	1/11		XP_047284829.1
MVK	XM_017019313.3 linkuse as main transcript	c.-161C>T		5_prime_UTR_variant	1/10		XP_016874802.1
MMAB	NR_038118.2 linkuse as main transcript	n.80G>A		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7 linkuse as main transcript	c.56G>A	p.Arg19His	missense_variant	1/9	1	NM_052845.4	ENSP00000445920	P1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46640

AN:

151780

Hom.:

7424

Cov.:

show subpopulations

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:

62944

AN:

234330

Hom.:

8724

AF XY:

0.265

AC XY:

34117

AN XY:

128630

show subpopulations

Gnomad AFR exome

AF:

0.414

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.124

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:

387945

AN:

1455900

Hom.:

53328

Cov.:

AF XY:

0.267

AC XY:

193143

AN XY:

724138

show subpopulations

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:

0.296

Gnomad4 NFE exome

AF:

0.267

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.308

AC:

46726

AN:

151898

Hom.:

7460

Cov.:

AF XY:

0.306

AC XY:

22689

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.400

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:

0.289

Hom.:

3047

Bravo

AF:

0.314

TwinsUK

AF:

0.265

AC:

983

ALSPAC

AF:

0.248

AC:

954

ESP6500AA

AF:

0.390

AC:

1710

ESP6500EA

AF:

0.267

AC:

2293

ExAC

AF:

0.266

AC:

31974

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria, cblB type

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;T

Eigen

Benign

-0.027

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.99

P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.1

N;.;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.33

MPC

0.57

ClinPred

0.031

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.083

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over