8-11808709-GTCCCACTCCCACTCCCACTCCCACTCCCAC-GTCCCACTCCCACTCCCACTCCCACTCCCACTCCCACTCCCAC

Variant names:

• chr8-11808709-G-GTCCCACTCCCAC
• rs71711801
• NM_004462.5:c.100-57_100-46dupCACTCCCACTCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BA1

The NM_001287750.2(FDFT1):​c.220_231dupCACTCCCACTCC​(p.His74_Ser77dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (39 hom., cov: 0)
  • Exomes 𝑓: 0.014 (282 hom.)
• Consequence: FDFT1 NM_001287750.2 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 15 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: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001287750.2
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.086 is higher than 0.05.

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.100-57_100-46dupCACTCCCACTCC		intron	N/A	NP_004453.3
	FDFT1	NM_001287750.2		c.220_231dupCACTCCCACTCC	p.His74_Ser77dup	conservative_inframe_insertion	Exon 1 of 7	NP_001274679.1	A0A1W2PQ47
	FDFT1	NM_001287742.2		c.100-57_100-46dupCACTCCCACTCC		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.100-57_100-46dupCACTCCCACTCC		intron	N/A	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000529464.5	TSL:1	n.100-930_100-919dupCACTCCCACTCC		intron	N/A	ENSP00000434770.1	E9PNJ2
	FDFT1	ENST00000525954.5	TSL:2	c.220_231dupCACTCCCACTCC	p.His74_Ser77dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000491537.1	A0A1W2PQ47

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2180 AN: 148906 Hom.: 39 Cov.: 0

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.00837

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0171

GnomAD4 exome AF: 0.0142 AC: 19353 AN: 1366006 Hom.: 282 Cov.: 0 AF XY: 0.0136 AC XY: 9115 AN XY: 672620

African (AFR) AF: 0.00486 AC: 153 AN: 31492

American (AMR) AF: 0.0886 AC: 3114 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 419 AN: 23468

East Asian (EAS) AF: 0.0194 AC: 694 AN: 35832

South Asian (SAS) AF: 0.00689 AC: 523 AN: 75936

European-Finnish (FIN) AF: 0.0125 AC: 500 AN: 39866

Middle Eastern (MID) AF: 0.00611 AC: 34 AN: 5568

European-Non Finnish (NFE) AF: 0.0122 AC: 12969 AN: 1061664

Other (OTH) AF: 0.0166 AC: 947 AN: 57050

GnomAD4 genome AF: 0.0147 AC: 2184 AN: 149018 Hom.: 39 Cov.: 0 AF XY: 0.0156 AC XY: 1136 AN XY: 72628

African (AFR) AF: 0.00557 AC: 223 AN: 40008

American (AMR) AF: 0.0479 AC: 722 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 65 AN: 3454

East Asian (EAS) AF: 0.0155 AC: 77 AN: 4952

South Asian (SAS) AF: 0.00838 AC: 39 AN: 4654

European-Finnish (FIN) AF: 0.0165 AC: 170 AN: 10294

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.0125 AC: 844 AN: 67316

Other (OTH) AF: 0.0169 AC: 35 AN: 2066

Alfa AF: 0.00603 Hom.: 2006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71711801; hg19: chr8-11666218; COSMIC: COSV99594790;