1-155319869-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002004.4(FDPS):c.1000A>G(p.Ser334Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FDPS NM_002004.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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]

RUSC1-AS1 (HGNC:26680): (RUSC1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FDPS	NM_002004.4	c.1000A>G	p.Ser334Gly	missense_variant	10/11	ENST00000368356.9
RUSC1-AS1	NR_145424.1	n.429T>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDPS	ENST00000368356.9	c.1000A>G	p.Ser334Gly	missense_variant	10/11	2	NM_002004.4
RUSC1-AS1	ENST00000443642.1	n.421T>C		non_coding_transcript_exon_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.1000A>G (p.S334G) alteration is located in exon 10 (coding exon 9) of the FDPS gene. This alteration results from a A to G substitution at nucleotide position 1000, causing the serine (S) at amino acid position 334 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.090	T;.;D;.;D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	T;.;.;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.073	T;T;T;T;T;T
Polyphen		0.50	.;.;P;.;P;.
Vest4		0.64
MutPred		0.91		.;.;Loss of stability (P = 0.0875);.;Loss of stability (P = 0.0875);.;
MVP		0.79
MPC		0.37
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.62
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1650082836; hg19: chr1-155289660;