rs34368092

Variant names:

• chr12-109581428-G-A
• rs34368092
• NM_000431.4:c.405G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000431.4(MVK):​c.405G>A​(p.Ser135Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.048 in 1,614,080 control chromosomes in the GnomAD database, including 2,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (285 hom., cov: 33)
  • Exomes 𝑓: 0.048 (2152 hom.)
• Consequence: MVK NM_000431.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -4.38
• Publications: 14 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]

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-109581428-G-A is Benign according to our data. Variant chr12-109581428-G-A is described in ClinVar as Benign. ClinVar VariationId is 129639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0607 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 11	NP_001107657.1	B2RDU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.405G>A	p.Ser135Ser	synonymous	Exon 5 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7787 AN: 152146 Hom.: 285 Cov.: 33

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0694

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0916

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0623

Gnomad OTH AF: 0.0503

GnomAD2 exomes AF: 0.0449 AC: 11281 AN: 251052 AF XY: 0.0448

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.0584

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0477 AC: 69725 AN: 1461814 Hom.: 2152 Cov.: 32 AF XY: 0.0477 AC XY: 34668 AN XY: 727218

African (AFR) AF: 0.0416 AC: 1394 AN: 33476

American (AMR) AF: 0.0259 AC: 1160 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1661 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0133 AC: 1151 AN: 86254

European-Finnish (FIN) AF: 0.0876 AC: 4675 AN: 53394

Middle Eastern (MID) AF: 0.0582 AC: 334 AN: 5742

European-Non Finnish (NFE) AF: 0.0509 AC: 56571 AN: 1112002

Other (OTH) AF: 0.0460 AC: 2775 AN: 60390

GnomAD4 genome AF: 0.0512 AC: 7795 AN: 152266 Hom.: 285 Cov.: 33 AF XY: 0.0507 AC XY: 3776 AN XY: 74456

African (AFR) AF: 0.0395 AC: 1640 AN: 41570

American (AMR) AF: 0.0306 AC: 468 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 241 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4816

European-Finnish (FIN) AF: 0.0916 AC: 972 AN: 10614

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0623 AC: 4234 AN: 67998

Other (OTH) AF: 0.0497 AC: 105 AN: 2112

Alfa AF: 0.0585 Hom.: 211

Bravo AF: 0.0446

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0588

EpiControl AF: 0.0528

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Hyperimmunoglobulin D with periodic fever (1)
-	-	1	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (1)
-	-	1	Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.64
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs34368092; hg19: chr12-110019233; COSMIC: COSV57331610; COSMIC: COSV57331610;