16-88653337-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002461.3(MVD):c.1085C>T(p.Pro362Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,600,368 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

MVD
NM_002461.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.37

Publications

3 publications found

Variant links:

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]

MVD Gene-Disease associations (from GenCC):

porokeratosis 7, multiple types
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
disseminated superficial actinic porokeratosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MVD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069036186).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3 link	c.1085C>T	p.Pro362Leu	missense_variant	Exon 9 of 10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MVD	ENST00000301012.8 link	c.1085C>T	p.Pro362Leu	missense_variant	Exon 9 of 10	1	NM_002461.3	ENSP00000301012.3	P53602
MVD	ENST00000565149.5 link	n.1644C>T		non_coding_transcript_exon_variant	Exon 5 of 6	1
MVD	ENST00000561895.1 link	n.366C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
MVD	ENST00000562981.1 link	n.248C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000290

AC:

AN:

234806

AF XY:

0.000335

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00602

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000836

Gnomad OTH exome

AF:

0.000353

GnomAD4 exome

AF:

0.000159

AC:

230

AN:

1448176

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

137

AN XY:

720748

show subpopulations

African (AFR)

AF:

0.0000618

AC:

AN:

32350

American (AMR)

AF:

0.0000750

AC:

AN:

40024

Ashkenazi Jewish (ASJ)

AF:

0.00614

AC:

157

AN:

25556

East Asian (EAS)

AF:

0.00

AC:

AN:

39450

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000361

AC:

AN:

1108522

Other (OTH)

AF:

0.000435

AC:

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000510

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000223

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MVD p.Pro362Leu variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201844867) and in control databases in 71 of 266178 chromosomes at a frequency of 0.0002667 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 57 of 9592 chromosomes (freq: 0.005942), Other in 2 of 6750 chromosomes (freq: 0.000296), European (non-Finnish) in 10 of 123014 chromosomes (freq: 0.000081), East Asian in 1 of 18628 chromosomes (freq: 0.000054) and South Asian in 1 of 28614 chromosomes (freq: 0.000035), but was not observed in the African, Latino, or European (Finnish) populations. The p.Pro362 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.42

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

M_CAP

Benign

0.028

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

3.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.10

Sift

Benign

0.65

Sift4G

Benign

0.47

Polyphen

0.066

Vest4

0.38

MVP

0.17

MPC

0.057

ClinPred

0.089

GERP RS

3.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.28

gMVP

0.59

Mutation Taster

=79/21

polymorphism

(source)

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

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16-88653337-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over