Genetic Variant NM_002004.4:c.673C>T (chr1-155318280-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002004.4(FDPS):c.673C>T(p.Leu225Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L225V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FDPS
NM_002004.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.67

Publications

2 publications found

Variant links:

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 links:

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

RUSC1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FDPS	NM_002004.4	MANE Select	c.673C>T	p.Leu225Phe	missense	Exon 6 of 11	NP_001995.1	P14324-1
FDPS	NM_001135821.2		c.673C>T	p.Leu225Phe	missense	Exon 6 of 11	NP_001129293.1	P14324-1
FDPS	NM_001135822.2		c.475C>T	p.Leu159Phe	missense	Exon 5 of 10	NP_001129294.1	P14324-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FDPS	ENST00000368356.9	TSL:2 MANE Select	c.673C>T	p.Leu225Phe	missense	Exon 6 of 11	ENSP00000357340.4	P14324-1
FDPS	ENST00000356657.10	TSL:1	c.673C>T	p.Leu225Phe	missense	Exon 6 of 11	ENSP00000349078.6	P14324-1
RUSC1-AS1	ENST00000543656.3	TSL:1	n.426G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249610

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.8

PhyloP100

5.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.54

Sift

Uncertain

0.013

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.80

MutPred

0.70

Loss of stability (P = 0.07)

MVP

0.89

MPC

0.91

ClinPred

0.98

GERP RS

3.8

Varity_R

0.85

gMVP

0.74

Mutation Taster

=14/86

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over