NM_000431.4:c.769-38C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000431.4(MVK):c.769-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,595,588 control chromosomes in the GnomAD database, including 23,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2123 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21830 hom. )

Consequence

MVK
NM_000431.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.464

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

porokeratosis 3, disseminated superficial actinic type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hyperimmunoglobulinemia D with periodic fever
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
mevalonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
disseminated superficial actinic porokeratosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
porokeratosis of Mibelli
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-109591203-C-T is Benign according to our data. Variant chr12-109591203-C-T is described in ClinVar as Benign. ClinVar VariationId is 439922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVK	NM_000431.4 link	c.769-38C>T		intron_variant	Intron 8 of 10	ENST00000228510.8	NP_000422.1	Q03426B2RDU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVK	ENST00000228510.8 link	c.769-38C>T		intron_variant	Intron 8 of 10	1	NM_000431.4	ENSP00000228510.3		Q03426

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24946

AN:

152136

Hom.:

2127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.0987

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.171

GnomAD2 exomes

AF:

0.159

AC:

39983

AN:

250774

AF XY:

0.160

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.172

AC:

248041

AN:

1443334

Hom.:

21830

Cov.:

AF XY:

0.170

AC XY:

122485

AN XY:

719038

show subpopulations

African (AFR)

AF:

0.164

AC:

5412

AN:

33042

American (AMR)

AF:

0.145

AC:

6466

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

4954

AN:

26050

East Asian (EAS)

AF:

0.160

AC:

6337

AN:

39602

South Asian (SAS)

AF:

0.138

AC:

11879

AN:

85878

European-Finnish (FIN)

AF:

0.107

AC:

5702

AN:

53126

Middle Eastern (MID)

AF:

0.203

AC:

1122

AN:

5540

European-Non Finnish (NFE)

AF:

0.179

AC:

195927

AN:

1095668

Other (OTH)

AF:

0.171

AC:

10242

AN:

59730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

11745

23489

35234

46978

58723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6864

13728

20592

27456

34320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.164

AC:

24954

AN:

152254

Hom.:

2123

Cov.:

AF XY:

0.158

AC XY:

11788

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.168

AC:

6991

AN:

41544

American (AMR)

AF:

0.154

AC:

2353

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

665

AN:

3472

East Asian (EAS)

AF:

0.141

AC:

729

AN:

5174

South Asian (SAS)

AF:

0.130

AC:

626

AN:

4828

European-Finnish (FIN)

AF:

0.0987

AC:

1049

AN:

10626

Middle Eastern (MID)

AF:

0.178

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.175

AC:

11924

AN:

67998

Other (OTH)

AF:

0.174

AC:

368

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1084

2168

3251

4335

5419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.174

Hom.:

445

Bravo

AF:

0.170

Asia WGS

AF:

0.150

AC:

520

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22246419, 27884173, 27190114) -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.4

(source)

DANN

Benign

0.74

PhyloP100

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over