chr12-109591234-T-G

Position:

chr12-109591234-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000431.4(MVK):c.769-7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,613,976 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 70 hom. )

Consequence

MVK
NM_000431.4 splice_region, intron

Scores

Splicing: ADA: 0.0002640

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 0.654

Variant links:

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]

MVK links:

MVK (HGNC:):

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 (BayesDel_noAF=-0.83).

BP6

Variant 12-109591234-T-G is Benign according to our data. Variant chr12-109591234-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 97620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109591234-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00416 (633/152346) while in subpopulation SAS AF= 0.0195 (94/4826). AF 95% confidence interval is 0.0163. There are 2 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.769-7T>G		splice_region_variant, intron_variant		ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.769-7T>G		splice_region_variant, intron_variant		1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00662

AC:

1665

AN:

251394

Hom.:

AF XY:

0.00776

AC XY:

1054

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00543

Gnomad ASJ exome

AF:

0.0181

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0227

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00474

AC:

6931

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

3897

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00588

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0225

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00326

Gnomad4 OTH exome

AF:

0.00687

GnomAD4 genome

AF:

0.00416

AC:

633

AN:

152346

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

349

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00460

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00486

Hom.:

Bravo

AF:

0.00418

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 27535533, 22246419, 25525159, 27884173, 24411001, 23006543, 28137891) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MVK: BP4, BS1, BS2 -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hyperimmunoglobulin D with periodic fever

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

Mevalonic aciduria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Nemaline myopathy 5

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous c.769-7T>G variant in MVK has been identified in at least 2 individuals including 1 individual with unknown phenotype and other variants in cis, and 1 individual with mevalonate kinase deficiency (Touitou & Domingo-Rittore, personal communication to Infevers database, 2004; PMID: 22246419), and has been identified in >2% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive mevalonic kinase deficiency. -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.0

DANN

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.038

SpliceAI score (max)

0.010

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