NM_004462.5:c.100-85G>C

Variant names:

• chr8-11808709-G-C
• rs750848649
• NM_004462.5:c.100-85G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004462.5(FDFT1):​c.100-85G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000043 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FDFT1 NM_004462.5 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.07
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16063866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004462.5. 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.100-85G>C		intron	N/A	NP_004453.3
	FDFT1	NM_001287750.2		c.192G>C	p.Gln64His	missense	Exon 1 of 7	NP_001274679.1	A0A1W2PQ47
	FDFT1	NM_001287742.2		c.100-85G>C		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.100-85G>C		intron	N/A	ENSP00000220584.4	P37268-1
	FDFT1	ENST00000529464.5	TSL:1	n.100-958G>C		intron	N/A	ENSP00000434770.1	E9PNJ2
	FDFT1	ENST00000525954.5	TSL:2	c.192G>C	p.Gln64His	missense	Exon 1 of 7	ENSP00000491537.1	A0A1W2PQ47

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 148922 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000432 AC: 59 AN: 1366046 Hom.: 1 Cov.: 32 AF XY: 0.0000461 AC XY: 31 AN XY: 672634

African (AFR) AF: 0.00 AC: 0 AN: 31492

American (AMR) AF: 0.000114 AC: 4 AN: 35138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23468

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35834

South Asian (SAS) AF: 0.0000658 AC: 5 AN: 75938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.0000424 AC: 45 AN: 1061694

Other (OTH) AF: 0.0000175 AC: 1 AN: 57048

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000134 AC: 2 AN: 148922 Hom.: 0 Cov.: 24 AF XY: 0.0000276 AC XY: 2 AN XY: 72512

African (AFR) AF: 0.00 AC: 0 AN: 39890

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67330

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.65
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.16	T
PhyloP100		2.1
GERP RS		-2.1
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.23
Mutation Taster		=100/0	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: rs750848649; hg19: chr8-11666218;