12-109579954-C-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.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:9

Conservation

PhyloP100: -2.00

Publications

9 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
mevalonate kinase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mevalonic aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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=-0.86).

BP6

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MVK	NM_000431.4	MANE Select	c.371+8C>T	splice_region intron	N/A	NP_000422.1	Q03426
MVK	NM_001414512.1		c.371+8C>T	splice_region intron	N/A	NP_001401441.1
MVK	NM_001114185.3		c.371+8C>T	splice_region intron	N/A	NP_001107657.1	B2RDU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MVK	ENST00000228510.8	TSL:1 MANE Select	c.371+8C>T	splice_region intron	N/A	ENSP00000228510.3	Q03426
MVK	ENST00000546277.6	TSL:5	c.371+8C>T	splice_region intron	N/A	ENSP00000438153.2	Q03426
MVK	ENST00000878306.1		c.371+8C>T	splice_region intron	N/A	ENSP00000548365.1

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

GnomAD2 exomes

AF:

0.0587

AC:

14747

AN:

251376

AF XY:

0.0613

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 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

African (AFR)

AF:

0.0128

AC:

428

AN:

33478

American (AMR)

AF:

0.0327

AC:

1461

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0664

AC:

1736

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0415

AC:

3576

AN:

86256

European-Finnish (FIN)

AF:

0.0655

AC:

3496

AN:

53386

Middle Eastern (MID)

AF:

0.0916

AC:

528

AN:

5764

European-Non Finnish (NFE)

AF:

0.0832

AC:

92568

AN:

1111964

Other (OTH)

AF:

0.0647

AC:

3908

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5766

11532

17298

23064

28830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3284

6568

9852

13136

16420

<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:

0.0535

AC:

8140

AN:

152232

Hom.:

298

Cov.:

AF XY:

0.0524

AC XY:

3897

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0147

AC:

612

AN:

41544

American (AMR)

AF:

0.0389

AC:

595

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0585

AC:

203

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0326

AC:

157

AN:

4814

European-Finnish (FIN)

AF:

0.0667

AC:

706

AN:

10590

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0824

AC:

5602

AN:

68002

Other (OTH)

AF:

0.0639

AC:

135

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

404

808

1212

1616

2020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0551

Hom.:

136

Bravo

AF:

0.0506

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hyperimmunoglobulin D with periodic fever (1)

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

Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.80

(source)

DANN

Benign

0.63

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over