NM_002004.4:c.-1-98T>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002004.4(FDPS):​c.-1-98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 953,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: FDPS NM_002004.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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>C		intron	N/A	NP_001995.1	P14324-1
	FDPS	NM_001135821.2		c.-1-98T>C		intron	N/A	NP_001129293.1	P14324-1
	FDPS	NM_001135822.2		c.-1-373T>C		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>C		intron	N/A	ENSP00000357340.4	P14324-1
	FDPS	ENST00000356657.10	TSL:1	c.-1-98T>C		intron	N/A	ENSP00000349078.6	P14324-1
	FDPS	ENST00000851541.1		c.-99T>C		5_prime_UTR	Exon 2 of 11	ENSP00000521600.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 953798 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 468906

African (AFR) AF: 0.00 AC: 0 AN: 21854

American (AMR) AF: 0.00 AC: 0 AN: 19036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16108

East Asian (EAS) AF: 0.00 AC: 0 AN: 32714

South Asian (SAS) AF: 0.00 AC: 0 AN: 47584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00000137 AC: 1 AN: 730812

Other (OTH) AF: 0.00 AC: 0 AN: 41714

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.51
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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;