8-11802851-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004462.5(FDFT1):​c.19C>T​(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L7I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FDFT1 NM_004462.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 0 publications found

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]

FDFT1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• squalene synthase deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000255046 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004462.5. 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
	FDFT1	NM_004462.5	MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 8	NP_004453.3
	FDFT1	NM_001287742.2		c.19C>T	p.Leu7Phe	missense	Exon 3 of 10	NP_001274671.1	Q6IAX1
	FDFT1	NM_001287743.2		c.19C>T	p.Leu7Phe	missense	Exon 2 of 9	NP_001274672.1	P37268-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDFT1	ENST00000220584.9	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 1 of 8	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000527045.1	TSL:1	n.68C>T		non_coding_transcript_exon	Exon 1 of 2
	FDFT1	ENST00000529464.5	TSL:1	n.19C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000434770.1	E9PNJ2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.068
Eigen_PC	Benign	-0.057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.55		Loss of catalytic residue at L7 (P = 0.0419)
MVP		0.54
ClinPred		0.97	D
GERP RS		-0.38
PromoterAI		-0.021	Neutral
Varity_R		0.38
Mutation Taster		=82/18	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: rs574662343; hg19: chr8-11660360;