rs397514570

Positions:

• chr12-109590857-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000431.4(MVK):​c.764T>C​(p.Leu255Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000431.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-109590857-T-C is Pathogenic according to our data. Variant chr12-109590857-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39724.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.764T>C	p.Leu255Pro	missense_variant	8/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.764T>C	p.Leu255Pro	missense_variant	8/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Porokeratosis 3, disseminated superficial actinic type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T;T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.0063
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.75	.;.;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.8	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D;D;.;.
REVEL	Pathogenic	0.74
Sift	Benign	0.30	T;T;.;.
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.88	P;B;B;P
Vest4		0.85
MutPred		0.49		Loss of stability (P = 0.0198);.;.;Loss of stability (P = 0.0198);
MVP		0.98
MPC		0.85
ClinPred		0.67	D
GERP RS		1.8
Varity_R		0.66
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs397514570; hg19: chr12-110028662;