NM_002461.3:c.1104A>G

Variant names:

• chr16-88653318-T-C
• rs148833471
• NM_002461.3:c.1104A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002461.3(MVD):​c.1104A>G​(p.Lys368Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,599,146 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0074 (46 hom.)
• Consequence: MVD NM_002461.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.628
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-88653318-T-C is Benign according to our data. Variant chr16-88653318-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 790328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.628 with no splicing effect.
• BS2: High AC in GnomAd4 at 739 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3	c.1104A>G	p.Lys368Lys	synonymous_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.1104A>G	p.Lys368Lys	synonymous_variant	Exon 9 of 10	1	NM_002461.3	ENSP00000301012.3
MVD	ENST00000565149.5	n.1663A>G		non_coding_transcript_exon_variant	Exon 5 of 6	1
MVD	ENST00000561895.1	n.385A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
MVD	ENST00000562981.1	n.267A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 739 AN: 152106 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00491 AC: 1146 AN: 233340 AF XY: 0.00502

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000593

Gnomad FIN exome AF: 0.00691

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00741 AC: 10723 AN: 1446922 Hom.: 46 Cov.: 32 AF XY: 0.00732 AC XY: 5274 AN XY: 720102

African (AFR) AF: 0.00105 AC: 34 AN: 32238

American (AMR) AF: 0.00306 AC: 122 AN: 39898

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 83 AN: 25530

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39294

South Asian (SAS) AF: 0.00230 AC: 194 AN: 84380

European-Finnish (FIN) AF: 0.00709 AC: 370 AN: 52200

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5720

European-Non Finnish (NFE) AF: 0.00865 AC: 9582 AN: 1107874

Other (OTH) AF: 0.00545 AC: 326 AN: 59788

GnomAD4 genome AF: 0.00485 AC: 739 AN: 152224 Hom.: 4 Cov.: 34 AF XY: 0.00498 AC XY: 371 AN XY: 74428

African (AFR) AF: 0.00132 AC: 55 AN: 41548

American (AMR) AF: 0.00392 AC: 60 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 11 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00791 AC: 538 AN: 67992

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00606 Hom.: 3

Bravo AF: 0.00467

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MVD: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.32
DANN	Benign	0.65
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs148833471; hg19: chr16-88719726;