12-109579954-C-T

Variant summary

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

The NM_000431.4(MVK):c.371+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,614,022 control chromosomes in the GnomAD database, including 4,706 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 Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 298 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4408 hom. )

Consequence

MVK
NM_000431.4 splice_region, intron

Scores

Splicing: ADA: 0.0003080

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.00

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:

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=-0.86).

BP6

Variant 12-109579954-C-T is Benign according to our data. Variant chr12-109579954-C-T is described in ClinVar as [Benign]. Clinvar id is 256113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109579954-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4 linkuse as main transcript	c.371+8C>T		splice_region_variant, intron_variant		ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8 linkuse as main transcript	c.371+8C>T		splice_region_variant, intron_variant		1	NM_000431.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0535

AC:

8144

AN:

152114

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.0585

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0326

Gnomad FIN

AF:

0.0667

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0824

Gnomad OTH

AF:

0.0646

GnomAD3 exomes

AF:

0.0587

AC:

14747

AN:

251376

Hom.:

558

AF XY:

0.0613

AC XY:

8324

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.0303

Gnomad ASJ exome

AF:

0.0680

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0407

Gnomad FIN exome

AF:

0.0651

Gnomad NFE exome

AF:

0.0855

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0737

AC:

107707

AN:

1461790

Hom.:

4408

Cov.:

AF XY:

0.0733

AC XY:

53277

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0664

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0415

Gnomad4 FIN exome

AF:

0.0655

Gnomad4 NFE exome

AF:

0.0832

Gnomad4 OTH exome

AF:

0.0647

GnomAD4 genome

AF:

0.0535

AC:

8140

AN:

152232

Hom.:

298

Cov.:

AF XY:

0.0524

AC XY:

3897

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.0389

Gnomad4 ASJ

AF:

0.0585

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0326

Gnomad4 FIN

AF:

0.0667

Gnomad4 NFE

AF:

0.0824

Gnomad4 OTH

AF:

0.0639

Alfa

AF:

0.0555

Hom.:

136

Bravo

AF:

0.0506

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
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

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hyperimmunoglobulin D with periodic fever

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

0.80

Dann

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00031

dbscSNV1_RF

Benign

0.0

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