chr8-11808828-A-T

Variant names:

• chr8-11808828-A-T
• rs4731
• NM_004462.5:c.134A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004462.5(FDFT1):​c.134A>T​(p.Lys45Met) 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. 16/22 in silico tools predict a benign outcome for this variant. 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. K45R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FDFT1 NM_004462.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.629
• Publications: 24 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1611203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDFT1	NM_004462.5	c.134A>T	p.Lys45Met	missense_variant	Exon 2 of 8	ENST00000220584.9	NP_004453.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDFT1	ENST00000220584.9	c.134A>T	p.Lys45Met	missense_variant	Exon 2 of 8	1	NM_004462.5	ENSP00000220584.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T;T;T;T;.;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.88	.;.;D;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.5	L;L;.;L;L;.;.
PhyloP100		0.63
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	.;.;N;N;N;N;.
REVEL	Benign	0.090
Sift	Benign	0.11	.;.;T;T;T;T;.
Sift4G	Benign	0.082	T;T;T;T;T;T;.
Polyphen		0.13	B;B;.;B;.;B;.
Vest4		0.32
MutPred		0.37		Loss of methylation at K45 (P = 0.0449);Loss of methylation at K45 (P = 0.0449);Loss of methylation at K45 (P = 0.0449);Loss of methylation at K45 (P = 0.0449);Loss of methylation at K45 (P = 0.0449);.;.;
MVP		0.44
ClinPred		0.11	T
GERP RS		3.6
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.36
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4731; hg19: chr8-11666337;