1-155309931-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002004.4(FDPS):​c.142C>T​(p.Arg48Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,604,308 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0066 ( 6 hom., cov: 31)
Exomes 𝑓: 0.0023 ( 15 hom. )

Consequence

FDPS
NM_002004.4 missense

Scores

2
6
10

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005872637).
BP6
Variant 1-155309931-C-T is Benign according to our data. Variant chr1-155309931-C-T is described in ClinVar as [Benign]. Clinvar id is 3042548.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00665 (1012/152252) while in subpopulation AFR AF= 0.019 (791/41540). AF 95% confidence interval is 0.0179. There are 6 homozygotes in gnomad4. There are 485 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1012 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FDPSNM_002004.4 linkc.142C>T p.Arg48Cys missense_variant Exon 2 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.142C>T p.Arg48Cys missense_variant Exon 2 of 11 2 NM_002004.4 ENSP00000357340.4 P14324-1

Frequencies

GnomAD3 genomes
AF:
0.00665
AC:
1011
AN:
152134
Hom.:
6
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0191
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00334
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00160
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00191
Gnomad OTH
AF:
0.00813
GnomAD3 exomes
AF:
0.00291
AC:
705
AN:
242260
Hom.:
9
AF XY:
0.00244
AC XY:
321
AN XY:
131536
show subpopulations
Gnomad AFR exome
AF:
0.0207
Gnomad AMR exome
AF:
0.00249
Gnomad ASJ exome
AF:
0.000718
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000267
Gnomad FIN exome
AF:
0.00161
Gnomad NFE exome
AF:
0.00222
Gnomad OTH exome
AF:
0.00288
GnomAD4 exome
AF:
0.00226
AC:
3279
AN:
1452056
Hom.:
15
Cov.:
32
AF XY:
0.00214
AC XY:
1545
AN XY:
720624
show subpopulations
Gnomad4 AFR exome
AF:
0.0192
Gnomad4 AMR exome
AF:
0.00291
Gnomad4 ASJ exome
AF:
0.000694
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000198
Gnomad4 FIN exome
AF:
0.000980
Gnomad4 NFE exome
AF:
0.00202
Gnomad4 OTH exome
AF:
0.00297
GnomAD4 genome
AF:
0.00665
AC:
1012
AN:
152252
Hom.:
6
Cov.:
31
AF XY:
0.00652
AC XY:
485
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0190
Gnomad4 AMR
AF:
0.00334
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00160
Gnomad4 NFE
AF:
0.00191
Gnomad4 OTH
AF:
0.00805
Alfa
AF:
0.00281
Hom.:
6
Bravo
AF:
0.00720
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.0202
AC:
89
ESP6500EA
AF:
0.00163
AC:
14
ExAC
AF:
0.00323
AC:
392
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

FDPS-related disorder Benign:1
Sep 24, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.12
T;T;T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.89
.;D;D;D
MetaRNN
Benign
0.0059
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.1
M;.;M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.31
N;.;N;.
REVEL
Benign
0.19
Sift
Pathogenic
0.0
D;.;D;.
Sift4G
Uncertain
0.010
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.68
MVP
0.59
MPC
1.2
ClinPred
0.037
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.19
gMVP
0.23

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

LitVar

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

Other links and lift over

dbSNP: rs35362111; hg19: chr1-155279722; COSMIC: COSV99054631; API