1-155318280-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002004.4(FDPS):​c.673C>T​(p.Leu225Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L225V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FDPS
NM_002004.4 missense

Scores

3
11
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.67
Variant links:
Genes affected
FDPS (HGNC:3631): (farnesyl diphosphate synthase) This gene encodes an enzyme that catalyzes the production of geranyl pyrophosphate and farnesyl pyrophosphate from isopentenyl pyrophosphate and dimethylallyl pyrophosphate. The resulting product, farnesyl pyrophosphate, is a key intermediate in cholesterol and sterol biosynthesis, a substrate for protein farnesylation and geranylgeranylation, and a ligand or agonist for certain hormone receptors and growth receptors. Drugs that inhibit this enzyme prevent the post-translational modifications of small GTPases and have been used to treat diseases related to bone resorption. Multiple pseudogenes have been found on chromosomes 1, 7, 14, 15, 21 and X. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]
RUSC1-AS1 (HGNC:26680): (RUSC1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FDPSNM_002004.4 linkc.673C>T p.Leu225Phe missense_variant Exon 6 of 11 ENST00000368356.9 NP_001995.1 P14324-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FDPSENST00000368356.9 linkc.673C>T p.Leu225Phe missense_variant Exon 6 of 11 2 NM_002004.4 ENSP00000357340.4 P14324-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;.;D;.;T;D;.
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.81
T;.;.;.;T;T;T
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.8
.;.;M;.;.;M;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.4
.;D;D;.;.;D;.
REVEL
Uncertain
0.54
Sift
Uncertain
0.013
.;D;D;.;.;D;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D
Polyphen
0.99
.;.;D;.;.;D;.
Vest4
0.80
MutPred
0.70
.;.;Loss of stability (P = 0.07);.;Loss of stability (P = 0.07);Loss of stability (P = 0.07);.;
MVP
0.89
MPC
0.91
ClinPred
0.98
D
GERP RS
3.8
Varity_R
0.85
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140056889; hg19: chr1-155288071; API