16-88653337-G-A

Position:

• chr16-88653337-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MVD	NM_002461.3	c.1085C>T	p.Pro362Leu	missense_variant	9/10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVD	ENST00000301012.8	c.1085C>T	p.Pro362Leu	missense_variant	9/10	1	NM_002461.3	ENSP00000301012.3
MVD	ENST00000565149.5	n.1644C>T		non_coding_transcript_exon_variant	5/6	1
MVD	ENST00000561895.1	n.366C>T		non_coding_transcript_exon_variant	2/3	2
MVD	ENST00000562981.1	n.248C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152192 Hom.: 0 Cov.: 34

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

GnomAD3 exomes AF: 0.000290 AC: 68 AN: 234806 Hom.: 0 AF XY: 0.000335 AC XY: 43 AN XY: 128272

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 SAS exome AF: 0.0000349

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.: 2 Cov.: 32 AF XY: 0.000190 AC XY: 137 AN XY: 720748

Gnomad4 AFR exome AF: 0.0000618

Gnomad4 AMR exome AF: 0.0000750

Gnomad4 ASJ exome AF: 0.00614

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.000435

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152192 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000223 AC: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.72
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.10
Sift	Benign	0.65	T
Sift4G	Benign	0.47	T
Polyphen		0.066	B
Vest4		0.38
MVP		0.17
MPC		0.057
ClinPred		0.089	T
GERP RS		3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.28
gMVP		0.59

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: rs201844867; hg19: chr16-88719745; COSMIC: COSV55368399; COSMIC: COSV55368399;