rs755948940

chr16-88655221-T-Cchr16-88655221-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Moderate PP5_Moderate

The NM_002461.3(MVD):c.875A>G(p.Asn292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000007 in 1,571,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N292H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MVD NM_002461.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.17

Genes affected

MVD (HGNC:7529): (mevalonate diphosphate decarboxylase) The enzyme mevalonate pyrophosphate decarboxylase catalyzes the conversion of mevalonate pyrophosphate into isopentenyl pyrophosphate in one of the early steps in cholesterol biosynthesis. It decarboxylates and dehydrates its substrate while hydrolyzing ATP. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 16-88655221-T-C is Pathogenic according to our data. Variant chr16-88655221-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 253040.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVD	NM_002461.3	c.875A>G	p.Asn292Ser	missense_variant	7/10	ENST00000301012.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVD	ENST00000301012.8	c.875A>G	p.Asn292Ser	missense_variant	7/10	1	NM_002461.3	P1
MVD	ENST00000565149.5	n.1434A>G		non_coding_transcript_exon_variant	3/6	1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000543 AC: 1 AN: 184144 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 98138

Gnomad AFR exome AF: 0.0000915

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000493 AC: 7 AN: 1418814 Hom.: 0 Cov.: 32 AF XY: 0.00000713 AC XY: 5 AN XY: 701620

Gnomad4 AFR exome AF: 0.0000919

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000840 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Porokeratosis 7, multiple types Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The amino acid Asn at position 292 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Asn292Ser in MVD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Asn292Ser variant is reported in gnomAD with the allele frequency of 0.00000928 and is novel (not in any individuals) in 1000 Genomes. It is a hotspot mutation and along with c.746T>C variant accounts for 81% cases (Zhang Z et al, Qian W et al). For these reasons, this variant has been classified as Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.70		Gain of glycosylation at N292 (P = 0.0373);
MVP		0.27
MPC		0.32
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.66
gMVP		0.86

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: rs755948940; hg19: chr16-88721629;