chr1-155309691-T-G

Variant names:

• chr1-155309691-T-G
• rs2297480
• NM_002004.4:c.-1-98T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002004.4(FDPS):​c.-1-98T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,103,806 control chromosomes in the GnomAD database, including 46,879 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (6847 hom., cov: 31)
  • Exomes 𝑓: 0.27 (40032 hom.)
• Consequence: FDPS NM_002004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 68 publications found

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]

FDPS Gene-Disease associations (from GenCC):

• porokeratosis 9, multiple types

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDPS	NM_002004.4	MANE Select	c.-1-98T>G		intron	N/A	NP_001995.1	P14324-1
	FDPS	NM_001135821.2		c.-1-98T>G		intron	N/A	NP_001129293.1	P14324-1
	FDPS	NM_001135822.2		c.-1-373T>G		intron	N/A	NP_001129294.1	P14324-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDPS	ENST00000368356.9	TSL:2 MANE Select	c.-1-98T>G		intron	N/A	ENSP00000357340.4	P14324-1
	FDPS	ENST00000356657.10	TSL:1	c.-1-98T>G		intron	N/A	ENSP00000349078.6	P14324-1
	FDPS	ENST00000851541.1		c.-99T>G		5_prime_UTR	Exon 2 of 11	ENSP00000521600.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43742 AN: 151904 Hom.: 6833 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.273 AC: 259665 AN: 951786 Hom.: 40032 Cov.: 12 AF XY: 0.272 AC XY: 127091 AN XY: 467952

African (AFR) AF: 0.300 AC: 6541 AN: 21804

American (AMR) AF: 0.341 AC: 6490 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 3653 AN: 16090

East Asian (EAS) AF: 0.725 AC: 23695 AN: 32696

South Asian (SAS) AF: 0.288 AC: 13679 AN: 47478

European-Finnish (FIN) AF: 0.284 AC: 11653 AN: 41000

Middle Eastern (MID) AF: 0.165 AC: 480 AN: 2904

European-Non Finnish (NFE) AF: 0.249 AC: 181875 AN: 729148

Other (OTH) AF: 0.278 AC: 11599 AN: 41652

GnomAD4 genome AF: 0.288 AC: 43774 AN: 152020 Hom.: 6847 Cov.: 31 AF XY: 0.291 AC XY: 21602 AN XY: 74318

African (AFR) AF: 0.298 AC: 12345 AN: 41458

American (AMR) AF: 0.294 AC: 4499 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3470

East Asian (EAS) AF: 0.699 AC: 3611 AN: 5164

South Asian (SAS) AF: 0.311 AC: 1500 AN: 4822

European-Finnish (FIN) AF: 0.300 AC: 3170 AN: 10574

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17127 AN: 67940

Other (OTH) AF: 0.284 AC: 598 AN: 2108

Alfa AF: 0.257 Hom.: 8292

Bravo AF: 0.294

Asia WGS AF: 0.499 AC: 1736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.47
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2297480; hg19: chr1-155279482; COSMIC: COSV63115029;