16-88654746-G-A

Variant names:

• chr16-88654746-G-A
• rs1488556161
• NM_002461.3:c.959C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002461.3(MVD):​c.959C>T​(p.Ala320Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MVD NM_002461.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35
• Publications: 1 publications found

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, G2P, Labcorp Genetics (formerly Invitae)
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23894152).

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.959C>T	p.Ala320Val	missense	Exon 8 of 10	NP_002452.1	P53602

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVD	ENST00000301012.8	TSL:1 MANE Select	c.959C>T	p.Ala320Val	missense	Exon 8 of 10	ENSP00000301012.3	P53602
	MVD	ENST00000565149.5	TSL:1	n.1518C>T		non_coding_transcript_exon	Exon 4 of 6
	MVD	ENST00000899622.1		c.1079C>T	p.Ala360Val	missense	Exon 9 of 11	ENSP00000569681.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 241370 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.89e-7 AC: 1 AN: 1451250 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722054

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32722

American (AMR) AF: 0.00 AC: 0 AN: 42060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25800

East Asian (EAS) AF: 0.00 AC: 0 AN: 38900

South Asian (SAS) AF: 0.00 AC: 0 AN: 84564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108650

Other (OTH) AF: 0.00 AC: 0 AN: 59944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.036
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		0.11	B
Vest4		0.42
MutPred		0.47		Loss of catalytic residue at A320 (P = 0.2897)
MVP		0.16
MPC		0.054
ClinPred		0.23	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.49

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

Other links and lift over

dbSNP: rs1488556161; hg19: chr16-88721154;