chr8-11808562-G-C

Variant names:

• chr8-11808562-G-C
• rs181750463
• NM_004462.5:c.100-232G>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001287750.2(FDFT1):​c.45G>C​(p.Lys15Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,366,542 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (50 hom.)
• Consequence: FDFT1 NM_001287750.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.26

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013361603).
• BP6: Variant 8-11808562-G-C is Benign according to our data. Variant chr8-11808562-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1049617.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDFT1	NM_004462.5	c.100-232G>C		intron_variant	Intron 1 of 7	ENST00000220584.9	NP_004453.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDFT1	ENST00000220584.9	c.100-232G>C		intron_variant	Intron 1 of 7	1	NM_004462.5	ENSP00000220584.4

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00799 AC: 9707 AN: 1214276 Hom.: 50 Cov.: 63 AF XY: 0.00778 AC XY: 4558 AN XY: 586070

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000415

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00925

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152266 Hom.: 3 Cov.: 33 AF XY: 0.00384 AC XY: 286 AN XY: 74444

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00815

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.00483

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FDFT1: BS2 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FDFT1 p.Lys15Asn variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs181750463) and in control databases in 116 of 31288 chromosomes at a frequency of 0.003707 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 90 of 15378 chromosomes (freq: 0.005853), Other in 5 of 1080 chromosomes (freq: 0.00463), Latino in 2 of 848 chromosomes (freq: 0.002358), African in 16 of 8660 chromosomes (freq: 0.001848) and European (Finnish) in 3 of 3474 chromosomes (freq: 0.000864), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys15 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

FDFT1-related disorder Benign:1

Feb 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.91
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.013	T
GERP RS		3.5
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs181750463; hg19: chr8-11666071;