8-11802853-T-C

Variant names:

• chr8-11802853-T-C
• rs1047643
• NM_004462.5:c.21T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001287756.2(FDFT1):​c.7T>C​(p.Trp3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,610,252 control chromosomes in the GnomAD database, including 22,999 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 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: 𝑓 0.19 (3583 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19416 hom.)
• Consequence: FDFT1 NM_001287756.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 23 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000255046 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287756.2. 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.21T>C	p.Leu7Leu	synonymous	Exon 1 of 8	NP_004453.3
	FDFT1	NM_001287756.2		c.7T>C	p.Trp3Arg	missense	Exon 1 of 5	NP_001274685.1	B4DWP0
	FDFT1	NM_001287742.2		c.21T>C	p.Leu7Leu	synonymous	Exon 3 of 10	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.21T>C	p.Leu7Leu	synonymous	Exon 1 of 8	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000527045.1	TSL:1	n.70T>C		non_coding_transcript_exon	Exon 1 of 2
	FDFT1	ENST00000529464.5	TSL:1	n.21T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000434770.1	E9PNJ2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29606 AN: 152180 Hom.: 3579 Cov.: 34

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0871

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.130 AC: 31689 AN: 243426 AF XY: 0.128

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0841

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0916

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.156 AC: 227142 AN: 1457954 Hom.: 19416 Cov.: 33 AF XY: 0.153 AC XY: 111263 AN XY: 725062

African (AFR) AF: 0.352 AC: 11715 AN: 33262

American (AMR) AF: 0.0900 AC: 3995 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3958 AN: 26008

East Asian (EAS) AF: 0.0115 AC: 454 AN: 39628

South Asian (SAS) AF: 0.107 AC: 9178 AN: 85584

European-Finnish (FIN) AF: 0.0932 AC: 4952 AN: 53146

Middle Eastern (MID) AF: 0.174 AC: 1000 AN: 5740

European-Non Finnish (NFE) AF: 0.164 AC: 182237 AN: 1109990

Other (OTH) AF: 0.160 AC: 9653 AN: 60208

GnomAD4 genome AF: 0.195 AC: 29641 AN: 152298 Hom.: 3583 Cov.: 34 AF XY: 0.185 AC XY: 13813 AN XY: 74470

African (AFR) AF: 0.343 AC: 14267 AN: 41540

American (AMR) AF: 0.128 AC: 1967 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3470

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5174

South Asian (SAS) AF: 0.102 AC: 494 AN: 4832

European-Finnish (FIN) AF: 0.0871 AC: 925 AN: 10622

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10815 AN: 68030

Other (OTH) AF: 0.183 AC: 388 AN: 2116

Alfa AF: 0.180 Hom.: 2060

Bravo AF: 0.203

Asia WGS AF: 0.0770 AC: 270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.6
DANN	Benign	0.75
PhyloP100		1.4
PromoterAI		0.0053	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1047643; hg19: chr8-11660362; COSMIC: COSV55043146; COSMIC: COSV55043146;