8-11808709-GTCCCACTCCCACTCCCACTCCCACTCCCAC-GTCCCACTCCCACTCCCACTCCCACTCCCACTCCCACTCCCACTCCCAC

Variant names:

• chr8-11808709-G-GTCCCACTCCCACTCCCAC
• rs71711801
• NM_004462.5:c.100-63_100-46dupCACTCCCACTCCCACTCC

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001287750.2(FDFT1):​c.214_231dupCACTCCCACTCCCACTCC​(p.His72_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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 0)
  • Exomes 𝑓: 0.014 (189 hom.)
• Consequence: FDFT1 NM_001287750.2 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001287750.2
• BP6: Variant 8-11808709-G-GTCCCACTCCCACTCCCAC is Benign according to our data. Variant chr8-11808709-G-GTCCCACTCCCACTCCCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 3043487.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0511 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.100-63_100-46dupCACTCCCACTCCCACTCC		intron	N/A	NP_004453.3
	FDFT1	NM_001287750.2		c.214_231dupCACTCCCACTCCCACTCC	p.His72_Ser77dup	conservative_inframe_insertion	Exon 1 of 7	NP_001274679.1	A0A1W2PQ47
	FDFT1	NM_001287742.2		c.100-63_100-46dupCACTCCCACTCCCACTCC		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.100-63_100-46dupCACTCCCACTCCCACTCC		intron	N/A	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000529464.5	TSL:1	n.100-936_100-919dupCACTCCCACTCCCACTCC		intron	N/A	ENSP00000434770.1	E9PNJ2
	FDFT1	ENST00000525954.5	TSL:2	c.214_231dupCACTCCCACTCCCACTCC	p.His72_Ser77dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000491537.1	A0A1W2PQ47

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1662 AN: 148918 Hom.: 21 Cov.: 0

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0382

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00751

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.0136 AC: 18632 AN: 1366000 Hom.: 189 Cov.: 0 AF XY: 0.0137 AC XY: 9200 AN XY: 672602

African (AFR) AF: 0.00321 AC: 101 AN: 31492

American (AMR) AF: 0.0182 AC: 640 AN: 35138

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 776 AN: 23468

East Asian (EAS) AF: 0.000279 AC: 10 AN: 35834

South Asian (SAS) AF: 0.00849 AC: 645 AN: 75938

European-Finnish (FIN) AF: 0.00329 AC: 131 AN: 39866

Middle Eastern (MID) AF: 0.0563 AC: 313 AN: 5564

European-Non Finnish (NFE) AF: 0.0142 AC: 15123 AN: 1061656

Other (OTH) AF: 0.0157 AC: 893 AN: 57044

GnomAD4 genome AF: 0.0112 AC: 1662 AN: 149030 Hom.: 21 Cov.: 0 AF XY: 0.0104 AC XY: 759 AN XY: 72632

African (AFR) AF: 0.00320 AC: 128 AN: 40010

American (AMR) AF: 0.0188 AC: 284 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.0382 AC: 132 AN: 3456

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4952

South Asian (SAS) AF: 0.00774 AC: 36 AN: 4654

European-Finnish (FIN) AF: 0.00340 AC: 35 AN: 10296

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.0148 AC: 999 AN: 67318

Other (OTH) AF: 0.0189 AC: 39 AN: 2068

Alfa AF: 0.00804 Hom.: 2006

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	FDFT1-related disorder (1)
-	-	1	not specified (1)

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: COSV107273892;