chr1-155309931-C-T

Variant names:

• chr1-155309931-C-T
• rs35362111
• NM_002004.4:c.142C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002004.4(FDPS):​c.142C>T​(p.Arg48Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,604,308 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (15 hom.)
• Consequence: FDPS NM_002004.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.32
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005872637).
• BP6: Variant 1-155309931-C-T is Benign according to our data. Variant chr1-155309931-C-T is described in ClinVar as Benign. ClinVar VariationId is 3042548.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00665 (1012/152252) while in subpopulation AFR AF = 0.019 (791/41540). AF 95% confidence interval is 0.0179. There are 6 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1012 AD gene.

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.142C>T	p.Arg48Cys	missense	Exon 2 of 11	NP_001995.1	P14324-1
	FDPS	NM_001135821.2		c.142C>T	p.Arg48Cys	missense	Exon 2 of 11	NP_001129293.1	P14324-1
	FDPS	NM_001135822.2		c.-1-133C>T		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.142C>T	p.Arg48Cys	missense	Exon 2 of 11	ENSP00000357340.4	P14324-1
	FDPS	ENST00000356657.10	TSL:1	c.142C>T	p.Arg48Cys	missense	Exon 2 of 11	ENSP00000349078.6	P14324-1
	FDPS	ENST00000851541.1		c.142C>T	p.Arg48Cys	missense	Exon 2 of 11	ENSP00000521600.1

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1011 AN: 152134 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00291 AC: 705 AN: 242260 AF XY: 0.00244

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000718

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00288

GnomAD4 exome AF: 0.00226 AC: 3279 AN: 1452056 Hom.: 15 Cov.: 32 AF XY: 0.00214 AC XY: 1545 AN XY: 720624

African (AFR) AF: 0.0192 AC: 640 AN: 33306

American (AMR) AF: 0.00291 AC: 128 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.000694 AC: 18 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.000198 AC: 17 AN: 85732

European-Finnish (FIN) AF: 0.000980 AC: 52 AN: 53042

Middle Eastern (MID) AF: 0.00303 AC: 16 AN: 5280

European-Non Finnish (NFE) AF: 0.00202 AC: 2230 AN: 1105478

Other (OTH) AF: 0.00297 AC: 178 AN: 59838

GnomAD4 genome AF: 0.00665 AC: 1012 AN: 152252 Hom.: 6 Cov.: 31 AF XY: 0.00652 AC XY: 485 AN XY: 74434

African (AFR) AF: 0.0190 AC: 791 AN: 41540

American (AMR) AF: 0.00334 AC: 51 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68006

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00372 Hom.: 9

Bravo AF: 0.00720

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FDPS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.59
MPC		1.2
ClinPred		0.037	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.23
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs35362111; hg19: chr1-155279722; COSMIC: COSV99054631;