chr12-109591252-C-A

Variant names:

• chr12-109591252-C-A
• rs34975996
• NM_000431.4:c.780C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000431.4(MVK):​c.780C>A​(p.Ile260Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,614,200 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I260I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (19 hom.)
• Consequence: MVK NM_000431.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0290
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 12-109591252-C-A is Benign according to our data. Variant chr12-109591252-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 307099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.029 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00808 (1231/152358) while in subpopulation AFR AF = 0.0282 (1171/41582). AF 95% confidence interval is 0.0268. There are 19 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

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.780C>A	p.Ile260Ile	synonymous	Exon 9 of 11	NP_000422.1	Q03426
	MVK	NM_001414512.1		c.855C>A	p.Ile285Ile	synonymous	Exon 10 of 12	NP_001401441.1
	MVK	NM_001114185.3		c.780C>A	p.Ile260Ile	synonymous	Exon 9 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.780C>A	p.Ile260Ile	synonymous	Exon 9 of 11	ENSP00000228510.3	Q03426
	MVK	ENST00000546277.6	TSL:5	c.780C>A	p.Ile260Ile	synonymous	Exon 9 of 11	ENSP00000438153.2	Q03426
	MVK	ENST00000878306.1		c.780C>A	p.Ile260Ile	synonymous	Exon 9 of 11	ENSP00000548365.1

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152240 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00211 AC: 530 AN: 251438 AF XY: 0.00139

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000878 AC: 1283 AN: 1461842 Hom.: 19 Cov.: 33 AF XY: 0.000736 AC XY: 535 AN XY: 727220

African (AFR) AF: 0.0295 AC: 989 AN: 33476

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000827 AC: 92 AN: 1111986

Other (OTH) AF: 0.00194 AC: 117 AN: 60390

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152358 Hom.: 19 Cov.: 33 AF XY: 0.00739 AC XY: 551 AN XY: 74510

African (AFR) AF: 0.0282 AC: 1171 AN: 41582

American (AMR) AF: 0.00261 AC: 40 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68042

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00898

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Hyperimmunoglobulin D with periodic fever (1)
-	-	1	Mevalonic aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	3.8
DANN	Benign	0.71
PhyloP100		0.029
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34975996; hg19: chr12-110029057;