16-88653416-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002461.3(MVD):​c.1014-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MVD NM_002461.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004166
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452466 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722680

African (AFR) AF: 0.00 AC: 0 AN: 32776

American (AMR) AF: 0.00 AC: 0 AN: 42800

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

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108874

Other (OTH) AF: 0.00 AC: 0 AN: 59962

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.71
PhyloP100		-0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0020
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: rs79325107; hg19: chr16-88719824;