NM_002004.4:c.925-40T>G

Variant names:

• chr1-155319754-T-G
• rs11264361
• NM_002004.4:c.925-40T>G

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• Publications: 37 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]

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

ACMG classification

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

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDPS	ENST00000368356.9	TSL:2 MANE Select	c.925-40T>G		intron	N/A	ENSP00000357340.4
	FDPS	ENST00000356657.10	TSL:1	c.925-40T>G		intron	N/A	ENSP00000349078.6
	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.: 32

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

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.: 35 AF XY: 0.270 AC XY: 196282 AN XY: 726960

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

GnomAD4 genome AF: 0.269 AC: 40969 AN: 152084 Hom.: 6093 Cov.: 32 AF XY: 0.274 AC XY: 20364 AN XY: 74348

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: 62 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17131 AN: 67974

Other (OTH) AF: 0.270 AC: 571 AN: 2112

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
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)

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

Other links and lift over

dbSNP: rs11264361; hg19: chr1-155289545;