chr16-88653352-G-A

Variant names:

• chr16-88653352-G-A
• rs151006109
• NM_002461.3:c.1070C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002461.3(MVD):​c.1070C>T​(p.Ala357Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,596,464 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0042 (21 hom.)
• Consequence: MVD NM_002461.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.54
• Publications: 5 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, Labcorp Genetics (formerly Invitae), G2P
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007250488).
• BP6: Variant 16-88653352-G-A is Benign according to our data. Variant chr16-88653352-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2498675.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3	c.1070C>T	p.Ala357Val	missense_variant	Exon 9 of 10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVD	ENST00000301012.8	c.1070C>T	p.Ala357Val	missense_variant	Exon 9 of 10	1	NM_002461.3	ENSP00000301012.3
MVD	ENST00000565149.5	n.1629C>T		non_coding_transcript_exon_variant	Exon 5 of 6	1
MVD	ENST00000561895.1	n.351C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
MVD	ENST00000562981.1	n.233C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152132 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00379 AC: 876 AN: 230888 AF XY: 0.00391

Gnomad AFR exome AF: 0.000784

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.0000598

Gnomad FIN exome AF: 0.000426

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00502

GnomAD4 exome AF: 0.00417 AC: 6016 AN: 1444214 Hom.: 21 Cov.: 32 AF XY: 0.00407 AC XY: 2925 AN XY: 718852

African (AFR) AF: 0.00103 AC: 33 AN: 31980

American (AMR) AF: 0.00640 AC: 246 AN: 38438

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 70 AN: 25390

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39432

South Asian (SAS) AF: 0.000417 AC: 35 AN: 83880

European-Finnish (FIN) AF: 0.000384 AC: 20 AN: 52132

Middle Eastern (MID) AF: 0.00438 AC: 25 AN: 5708

European-Non Finnish (NFE) AF: 0.00483 AC: 5351 AN: 1107598

Other (OTH) AF: 0.00394 AC: 235 AN: 59656

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152250 Hom.: 2 Cov.: 34 AF XY: 0.00253 AC XY: 188 AN XY: 74444

African (AFR) AF: 0.000698 AC: 29 AN: 41544

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68010

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00425 Hom.: 3

Bravo AF: 0.00325

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MVD: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.039
Sift	Benign	0.32	T
Sift4G	Benign	0.33	T
Polyphen		0.0040	B
Vest4		0.16
MVP		0.12
MPC		0.053
ClinPred		0.0037	T
GERP RS		3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.060
gMVP		0.49
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151006109; hg19: chr16-88719760; COSMIC: COSV55368287; COSMIC: COSV55368287;