1-155309895-G-C

Variant names:

• chr1-155309895-G-C
• rs746782056
• NM_002004.4:c.106G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002004.4(FDPS):​c.106G>C​(p.Val36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,596,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V36M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FDPS NM_002004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09553942).

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.106G>C	p.Val36Leu	missense	Exon 2 of 11	NP_001995.1	P14324-1
	FDPS	NM_001135821.2		c.106G>C	p.Val36Leu	missense	Exon 2 of 11	NP_001129293.1	P14324-1
	FDPS	NM_001135822.2		c.-1-169G>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.106G>C	p.Val36Leu	missense	Exon 2 of 11	ENSP00000357340.4	P14324-1
	FDPS	ENST00000356657.10	TSL:1	c.106G>C	p.Val36Leu	missense	Exon 2 of 11	ENSP00000349078.6	P14324-1
	FDPS	ENST00000851541.1		c.106G>C	p.Val36Leu	missense	Exon 2 of 11	ENSP00000521600.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1444044 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716194

African (AFR) AF: 0.0000301 AC: 1 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 42236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39008

South Asian (SAS) AF: 0.00 AC: 0 AN: 84712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102332

Other (OTH) AF: 0.0000168 AC: 1 AN: 59534

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.010
Sift	Benign	0.088	T
Sift4G	Benign	0.083	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.11
Mutation Taster		=94/6	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746782056; hg19: chr1-155279686;