Genetic Variant NM_002461.3:c.941C>A (chr16-88654764-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002461.3(MVD):c.941C>A(p.Thr314Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T314S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MVD
NM_002461.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.71

Publications

0 publications found

Variant links:

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

MVD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MVD	NM_002461.3 link	c.941C>A	p.Thr314Asn	missense_variant	Exon 8 of 10	ENST00000301012.8	NP_002452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MVD	ENST00000301012.8 link	c.941C>A	p.Thr314Asn	missense_variant	Exon 8 of 10	1	NM_002461.3	ENSP00000301012.3	P53602
MVD	ENST00000565149.5 link	n.1500C>A		non_coding_transcript_exon_variant	Exon 4 of 6	1
MVD	ENST00000561895.1 link	n.222C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32508

American (AMR)

AF:

0.00

AC:

AN:

40562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25560

East Asian (EAS)

AF:

0.00

AC:

AN:

38914

South Asian (SAS)

AF:

0.00

AC:

AN:

83860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107214

Other (OTH)

AF:

0.00

AC:

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.1

PhyloP100

3.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.15

Sift

Uncertain

0.026

Sift4G

Benign

0.20

Polyphen

0.70

Vest4

0.76

MutPred

0.61

Loss of sheet (P = 0.1158);

MVP

0.31

MPC

0.094

ClinPred

0.95

GERP RS

4.4

Varity_R

0.37

gMVP

0.91

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

Publications

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NM_002461.3:c.941C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over