dbSNP rs755948940: MVD:p.Asn292Ile (chr16-88655221-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_002461.3(MVD):c.875A>T(p.Asn292Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,418,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N292H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MVD
NM_002461.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.17

Publications

0 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-88655221-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253040.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002461.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVD	NM_002461.3	MANE Select	c.875A>T	p.Asn292Ile	missense	Exon 7 of 10	NP_002452.1	P53602

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MVD	ENST00000301012.8	TSL:1 MANE Select	c.875A>T	p.Asn292Ile	missense	Exon 7 of 10	ENSP00000301012.3	P53602
MVD	ENST00000565149.5	TSL:1	n.1434A>T		non_coding_transcript_exon	Exon 3 of 6
MVD	ENST00000899622.1		c.995A>T	p.Asn332Ile	missense	Exon 8 of 11	ENSP00000569681.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1418816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32656

American (AMR)

AF:

0.00

AC:

AN:

37948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25344

East Asian (EAS)

AF:

0.00

AC:

AN:

37412

South Asian (SAS)

AF:

0.00

AC:

AN:

80672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1090250

Other (OTH)

AF:

0.00

AC:

AN:

58826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

4.0

PhyloP100

7.2

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-8.8

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.74

Loss of disorder (P = 0.049)

MVP

0.31

MPC

0.38

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.93

gMVP

0.93

Mutation Taster

=18/82

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over