Genetic Variant NM_002461.3:c.886G>A (chr16-88655210-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002461.3(MVD):c.886G>A(p.Gly296Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,563,022 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

MVD
NM_002461.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3 link	c.886G>A	p.Gly296Arg	missense_variant	Exon 7 of 10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MVD	ENST00000301012.8 link	c.886G>A	p.Gly296Arg	missense_variant	Exon 7 of 10	1	NM_002461.3	ENSP00000301012.3	P53602
MVD	ENST00000565149.5 link	n.1445G>A		non_coding_transcript_exon_variant	Exon 3 of 6	1
MVD	ENST00000569177.5 link	c.*175G>A		downstream_gene_variant		5		ENSP00000455131.1	H3BP35
MVD	ENST00000561895.1 link	n.-225G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000811

AC:

AN:

172576

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

91588

show subpopulations

Gnomad AFR exome

AF:

0.000197

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:

0.000141

Gnomad OTH exome

AF:

0.000424

GnomAD4 exome

AF:

0.000130

AC:

183

AN:

1410776

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

696928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000928

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000405

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000164

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000153

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.886G>A (p.G296R) alteration is located in exon 7 (coding exon 7) of the MVD gene. This alteration results from a G to A substitution at nucleotide position 886, causing the glycine (G) at amino acid position 296 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Benign

0.096

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.20

Sift

Benign

0.047

Sift4G

Uncertain

0.051

Polyphen

0.51

Vest4

0.69

MutPred

0.77

Gain of solvent accessibility (P = 0.0097);

MVP

0.29

MPC

0.10

ClinPred

0.61

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.45

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over