1-155309931-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (15 hom.)
• Consequence: FDPS NM_002004.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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 GnomAd at 1011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FDPS	NM_002004.4	c.142C>T	p.Arg48Cys	missense_variant	2/11	ENST00000368356.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDPS	ENST00000368356.9	c.142C>T	p.Arg48Cys	missense_variant	2/11	2	NM_002004.4

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1011 AN: 152134 Hom.: 6 Cov.: 31

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

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

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

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: criteria provided, single submitter

Submissions by phenotype

FDPS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

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
MetaRNN	Benign	0.0059	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	0.81	D;D;D
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

Other links and lift over

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