NM_002461.3:c.1012A>C

Variant names:

• chr16-88654693-T-G
• NM_002461.3:c.1012A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002461.3(MVD):​c.1012A>C​(p.Thr338Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,444,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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: 6.9e-7 (0 hom.)
• Consequence: MVD NM_002461.3 missense, splice_region
• Scores: Splicing: ADA: 0.008238
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.962

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09119272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3	c.1012A>C	p.Thr338Pro	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MVD	ENST00000301012.8	c.1012A>C	p.Thr338Pro	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_002461.3	ENSP00000301012.3
MVD	ENST00000565149.5	n.1571A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	1
MVD	ENST00000561895.1	n.293A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1444034 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.41
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.25	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.33		Loss of phosphorylation at T338 (P = 0.0384);
MVP		0.055
MPC		0.065
ClinPred		0.062	T
GERP RS		-1.0
Varity_R		0.31
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0082
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-88721101;