NM_002004.4:c.480+2075C>T

Variant names:

• chr1-155314470-C-T
• rs10796941
• NM_002004.4:c.480+2075C>T

Variant summary

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

The NM_002004.4(FDPS):​c.480+2075C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,314 control chromosomes in the GnomAD database, including 5,935 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 0.27 (5935 hom., cov: 30)
• Consequence: FDPS NM_002004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89
• Publications: 7 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: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDPS	NM_002004.4	c.480+2075C>T		intron_variant	Intron 4 of 10	ENST00000368356.9	NP_001995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDPS	ENST00000368356.9	c.480+2075C>T		intron_variant	Intron 4 of 10	2	NM_002004.4	ENSP00000357340.4

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40166 AN: 151194 Hom.: 5925 Cov.: 30

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.270

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40187 AN: 151314 Hom.: 5935 Cov.: 30 AF XY: 0.270 AC XY: 19944 AN XY: 73876

African (AFR) AF: 0.216 AC: 8914 AN: 41220

American (AMR) AF: 0.288 AC: 4378 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 785 AN: 3464

East Asian (EAS) AF: 0.718 AC: 3697 AN: 5150

South Asian (SAS) AF: 0.310 AC: 1480 AN: 4774

European-Finnish (FIN) AF: 0.301 AC: 3134 AN: 10426

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17081 AN: 67770

Other (OTH) AF: 0.267 AC: 560 AN: 2098

Alfa AF: 0.248 Hom.: 634

Bravo AF: 0.268

Asia WGS AF: 0.496 AC: 1726 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.43
PhyloP100		-1.9
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: rs10796941; hg19: chr1-155284261;