rs769971050

Variant names:

• chr1-154925181-C-A
• NM_006556.4:c.527G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-154925181-C-A
• chr1-154925181-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_006556.4(PMVK):​c.527G>T​(p.Arg176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PMVK NM_006556.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26

Genes affected

PMVK (HGNC:9141): (phosphomevalonate kinase) This gene encodes a peroxisomal enzyme that is a member of the galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase (GHMP) family of ATP-dependent enzymes. The encoded protein catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate, which is the fifth step in the mevalonate pathway of isoprenoid biosynthesis. Mutations in this gene are linked to certain types of porokeratosis including disseminated superficial porokeratosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PMVK_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06702441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMVK	NM_006556.4	c.527G>T	p.Arg176Leu	missense_variant	Exon 5 of 5	ENST00000368467.4	NP_006547.1
PMVK	NM_001323011.3	c.485G>T	p.Arg162Leu	missense_variant	Exon 5 of 5		NP_001309940.1
PMVK	NM_001323012.3	c.302G>T	p.Arg101Leu	missense_variant	Exon 5 of 5		NP_001309941.1
PMVK	NM_001348696.2	c.302G>T	p.Arg101Leu	missense_variant	Exon 5 of 5		NP_001335625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMVK	ENST00000368467.4	c.527G>T	p.Arg176Leu	missense_variant	Exon 5 of 5	1	NM_006556.4	ENSP00000357452.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0050
DANN	Benign	0.88
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.038
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.32		Gain of helix (P = 0.0128);
MVP		0.13
MPC		0.52
ClinPred		0.15	T
GERP RS		-7.4
Varity_R		0.11
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154897657;