12-109573660-G-A

Variant names:

• chr12-109573660-G-A
• rs66486014
• ENST00000546277.6:c.-15+89G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000546277.6(MVK):​c.-15+89G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 757,782 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (36 hom.)
• Consequence: MVK ENST00000546277.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.87
• Publications: 2 publications found

Genes affected

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]

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=-0.73).
• BP6: Variant 12-109573660-G-A is Benign according to our data. Variant chr12-109573660-G-A is described in ClinVar as Benign. ClinVar VariationId is 534562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00701 (1068/152360) while in subpopulation NFE AF = 0.0103 (704/68028). AF 95% confidence interval is 0.00971. There are 6 homozygotes in GnomAd4. There are 512 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000546277.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.-228G>A		upstream_gene	N/A	NP_000422.1
	MMAB	NM_052845.4	MANE Select	c.-180C>T		upstream_gene	N/A	NP_443077.1
	MVK	NM_001414512.1		c.-228G>A		upstream_gene	N/A	NP_001401441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000546277.6	TSL:5	c.-15+89G>A		intron	N/A	ENSP00000438153.2
	MVK	ENST00000539335.5	TSL:3	c.-6+89G>A		intron	N/A	ENSP00000440379.1
	MVK	ENST00000535044.1	TSL:4	n.231+89G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152242 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00887 AC: 5370 AN: 605422 Hom.: 36 Cov.: 7 AF XY: 0.00841 AC XY: 2684 AN XY: 319150

African (AFR) AF: 0.00202 AC: 33 AN: 16330

American (AMR) AF: 0.00482 AC: 145 AN: 30090

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 339 AN: 17966

East Asian (EAS) AF: 0.0000313 AC: 1 AN: 31952

South Asian (SAS) AF: 0.00166 AC: 98 AN: 59090

European-Finnish (FIN) AF: 0.00841 AC: 268 AN: 31878

Middle Eastern (MID) AF: 0.00421 AC: 10 AN: 2378

European-Non Finnish (NFE) AF: 0.0109 AC: 4177 AN: 383988

Other (OTH) AF: 0.00942 AC: 299 AN: 31750

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152360 Hom.: 6 Cov.: 33 AF XY: 0.00687 AC XY: 512 AN XY: 74504

African (AFR) AF: 0.00188 AC: 78 AN: 41596

American (AMR) AF: 0.00634 AC: 97 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 704 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00603 Hom.: 2

Bravo AF: 0.00663

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MMAB: BS1, BS2; MVK: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Jul 19, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		1.9
PromoterAI		0.23	Neutral
Mutation Taster		=300/0	polymorphism

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: rs66486014; hg19: chr12-110011465;