Genetic Variant FDPS:c.925-40T>G (chr1-155319754-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002004.4(FDPS):c.925-40T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,438 control chromosomes in the GnomAD database, including 65,708 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.27 ( 6093 hom., cov: 32)

Exomes 𝑓: 0.27 ( 59615 hom. )

Consequence

FDPS
NM_002004.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.409

Publications

37 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
FDPS	NM_002004.4	MANE Select	c.925-40T>G	intron	N/A	NP_001995.1	P14324-1
FDPS	NM_001135821.2		c.925-40T>G	intron	N/A	NP_001129293.1	P14324-1
FDPS	NM_001135822.2		c.727-40T>G	intron	N/A	NP_001129294.1	P14324-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FDPS	ENST00000368356.9	TSL:2 MANE Select	c.925-40T>G	intron	N/A	ENSP00000357340.4	P14324-1
FDPS	ENST00000356657.10	TSL:1	c.925-40T>G	intron	N/A	ENSP00000349078.6	P14324-1
RUSC1-AS1	ENST00000543656.3	TSL:1	n.310-1358A>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40945

AN:

151966

Hom.:

6084

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.287

Gnomad ASJ

AF:

0.226

Gnomad EAS

AF:

0.718

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.274

GnomAD2 exomes

AF:

0.309

AC:

77582

AN:

251396

AF XY:

0.302

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.389

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.722

Gnomad FIN exome

AF:

0.295

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.277

GnomAD4 exome

AF:

0.271

AC:

396465

AN:

1461354

Hom.:

59615

Cov.:

AF XY:

0.270

AC XY:

196282

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.231

AC:

7744

AN:

33476

American (AMR)

AF:

0.381

AC:

17017

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6182

AN:

26126

East Asian (EAS)

AF:

0.743

AC:

29495

AN:

39690

South Asian (SAS)

AF:

0.295

AC:

25480

AN:

86250

European-Finnish (FIN)

AF:

0.288

AC:

15371

AN:

53418

Middle Eastern (MID)

AF:

0.171

AC:

988

AN:

5764

European-Non Finnish (NFE)

AF:

0.250

AC:

277420

AN:

1111526

Other (OTH)

AF:

0.278

AC:

16768

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

14594

29188

43781

58375

72969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9812

19624

29436

39248

49060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.269

AC:

40969

AN:

152084

Hom.:

6093

Cov.:

AF XY:

0.274

AC XY:

20364

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.231

AC:

9571

AN:

41512

American (AMR)

AF:

0.288

AC:

4400

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

785

AN:

3466

East Asian (EAS)

AF:

0.718

AC:

3704

AN:

5160

South Asian (SAS)

AF:

0.310

AC:

1491

AN:

4816

European-Finnish (FIN)

AF:

0.299

AC:

3155

AN:

10560

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.252

AC:

17131

AN:

67974

Other (OTH)

AF:

0.270

AC:

571

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1501

3002

4502

6003

7504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.239

Hom.:

5527

Bravo

AF:

0.273

Asia WGS

AF:

0.498

AC:

1733

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.1

(source)

DANN

Benign

0.74

PhyloP100

0.41

BranchPoint Hunter

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over