8-11802851-C-G

Variant names:

• chr8-11802851-C-G
• rs574662343
• NM_004462.5:c.19C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004462.5(FDFT1):​c.19C>G​(p.Leu7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FDFT1 NM_004462.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

Genes affected

FDFT1 (HGNC:3629): (farnesyl-diphosphate farnesyltransferase 1) This gene encodes a membrane-associated enzyme located at a branch point in the mevalonate pathway. The encoded protein is the first specific enzyme in cholesterol biosynthesis, catalyzing the dimerization of two molecules of farnesyl diphosphate in a two-step reaction to form squalene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28683704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDFT1	NM_004462.5	c.19C>G	p.Leu7Val	missense_variant	Exon 1 of 8	ENST00000220584.9	NP_004453.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDFT1	ENST00000220584.9	c.19C>G	p.Leu7Val	missense_variant	Exon 1 of 8	1	NM_004462.5	ENSP00000220584.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244592 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132688

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459044 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.42	T;T;T;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	.;.;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.26	.;.;T;D;D;D
Sift4G	Uncertain	0.0050	D;D;T;D;D;D
Polyphen		0.94	P;P;.;P;.;P
Vest4		0.76
MutPred		0.54		Loss of catalytic residue at L7 (P = 0.029);Loss of catalytic residue at L7 (P = 0.029);Loss of catalytic residue at L7 (P = 0.029);Loss of catalytic residue at L7 (P = 0.029);Loss of catalytic residue at L7 (P = 0.029);Loss of catalytic residue at L7 (P = 0.029);
MVP		0.46
ClinPred		0.48	T
GERP RS		-0.38
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.11

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

LitVar

Other links and lift over

dbSNP: rs574662343; hg19: chr8-11660360;