8-11808562-G-T

Variant names:

• chr8-11808562-G-T
• rs181750463
• NM_004462.5:c.100-232G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001287750.2(FDFT1):​c.45G>T​(p.Lys15Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000824 in 1,214,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: FDFT1 NM_001287750.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38720322).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287750.2. 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.100-232G>T		intron	N/A	NP_004453.3
	FDFT1	NM_001287750.2		c.45G>T	p.Lys15Asn	missense	Exon 1 of 7	NP_001274679.1	A0A1W2PQ47
	FDFT1	NM_001287742.2		c.100-232G>T		intron	N/A	NP_001274671.1	Q6IAX1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDFT1	ENST00000220584.9	TSL:1 MANE Select	c.100-232G>T		intron	N/A	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000529464.5	TSL:1	n.100-1105G>T		intron	N/A	ENSP00000434770.1	E9PNJ2
	FDFT1	ENST00000525954.5	TSL:2	c.45G>T	p.Lys15Asn	missense	Exon 1 of 7	ENSP00000491537.1	A0A1W2PQ47

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.24e-7 AC: 1 AN: 1214280 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 586070

African (AFR) AF: 0.00 AC: 0 AN: 23610

American (AMR) AF: 0.00 AC: 0 AN: 12530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16524

East Asian (EAS) AF: 0.00 AC: 0 AN: 28976

South Asian (SAS) AF: 0.00 AC: 0 AN: 52962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3482

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 997252

Other (OTH) AF: 0.00 AC: 0 AN: 49998

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.97
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.39	T
PhyloP100		5.3
GERP RS		3.5
PromoterAI		0.13	Neutral
gMVP		0.26
Mutation Taster		=95/5	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: rs181750463; hg19: chr8-11666071;