1-155318722-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002004.4(FDPS):c.742A>C(p.Asn248His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FDPS NM_002004.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.456

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04907173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FDPS	NM_002004.4	c.742A>C	p.Asn248His	missense_variant	7/11	ENST00000368356.9
RUSC1-AS1	NR_145424.1	n.496-326T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDPS	ENST00000368356.9	c.742A>C	p.Asn248His	missense_variant	7/11	2	NM_002004.4
RUSC1-AS1	ENST00000443642.1	n.488-326T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 20, 2022

The c.742A>C (p.N248H) alteration is located in exon 7 (coding exon 6) of the FDPS gene. This alteration results from a A to C substitution at nucleotide position 742, causing the asparagine (N) at amino acid position 248 to be replaced by a histidine (H). 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	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.87
DEOGEN2	Benign	0.0078	T;.;T;.;T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.84	T;.;.;.;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.049	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.41	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;B;.
Vest4		0.12
MutPred		0.33		.;.;Loss of MoRF binding (P = 0.2071);.;Loss of MoRF binding (P = 0.2071);Loss of MoRF binding (P = 0.2071);.;
MVP		0.43
MPC		0.30
ClinPred		0.059	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.19

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155288513;