rs397514571

Positions:

• chr12-109576041-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000431.4(MVK):​c.122T>C​(p.Leu41Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MVK NM_000431.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.66

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 15) in uniprot entity KIME_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000431.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 12-109576041-T-C is Pathogenic according to our data. Variant chr12-109576041-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39728.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.122T>C	p.Leu41Pro	missense_variant	3/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.122T>C	p.Leu41Pro	missense_variant	3/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	.;T;D;T;.;.;T;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;.;.;T;T;T;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;.;D;D;D
Polyphen		1.0, 0.98	.;.;D;D;.;.;D;D
Vest4		0.92, 0.92, 0.90, 0.92
MutPred		0.90		Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);Gain of disorder (P = 0.0116);
MVP		0.99
MPC		1.5
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs397514571; hg19: chr12-110013846;