chr16-88653416-A-C

Variant names:

• chr16-88653416-A-C
• rs79325107
• NM_002461.3:c.1014-8T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002461.3(MVD):​c.1014-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,604,766 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.028 (193 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (154 hom.)
• Consequence: MVD NM_002461.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005020
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.139
• 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, Labcorp Genetics (formerly Invitae), G2P
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-88653416-A-C is Benign according to our data. Variant chr16-88653416-A-C is described in ClinVar as [Benign]. Clinvar id is 3055645.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3	c.1014-8T>G		splice_region_variant, intron_variant	Intron 8 of 9	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVD	ENST00000301012.8	c.1014-8T>G		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_002461.3	ENSP00000301012.3
MVD	ENST00000565149.5	n.1573-8T>G		splice_region_variant, intron_variant	Intron 4 of 5	1
MVD	ENST00000562981.1	n.169T>G		non_coding_transcript_exon_variant	Exon 1 of 2	2
MVD	ENST00000561895.1	n.295-8T>G		splice_region_variant, intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4217 AN: 152200 Hom.: 192 Cov.: 34

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00663 AC: 1568 AN: 236566 AF XY: 0.00487

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00253 AC: 3671 AN: 1452448 Hom.: 154 Cov.: 31 AF XY: 0.00218 AC XY: 1578 AN XY: 722678

African (AFR) AF: 0.0917 AC: 3004 AN: 32762

American (AMR) AF: 0.00442 AC: 189 AN: 42796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.000176 AC: 15 AN: 85218

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51910

Middle Eastern (MID) AF: 0.00279 AC: 16 AN: 5738

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1108874

Other (OTH) AF: 0.00555 AC: 333 AN: 59962

GnomAD4 genome AF: 0.0277 AC: 4223 AN: 152318 Hom.: 193 Cov.: 34 AF XY: 0.0269 AC XY: 2005 AN XY: 74472

African (AFR) AF: 0.0967 AC: 4017 AN: 41560

American (AMR) AF: 0.00934 AC: 143 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.00292 Hom.: 9

Bravo AF: 0.0305

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MVD-related disorder Benign:1

Jan 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.72
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.030		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: rs79325107; hg19: chr16-88719824;