rs62642482

Positions:

• chr17-82091249-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004104.5(FASN):​c.1465G>A​(p.Glu489Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,600,482 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (6 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.467

Genes affected

FASN (HGNC:3594): (fatty acid synthase) The enzyme encoded by this gene is a multifunctional protein. Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. In some cancer cell lines, this protein has been found to be fused with estrogen receptor-alpha (ER-alpha), in which the N-terminus of FAS is fused in-frame with the C-terminus of ER-alpha. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055253804).
• BP6: Variant 17-82091249-C-T is Benign according to our data. Variant chr17-82091249-C-T is described in ClinVar as [Benign]. Clinvar id is 462005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.1465G>A	p.Glu489Lys	missense_variant	9/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.1465G>A	p.Glu489Lys	missense_variant	9/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.1465G>A	p.Glu489Lys	missense_variant	9/43	1	NM_004104.5	ENSP00000304592	P1
FASN	ENST00000634990.1	c.1465G>A	p.Glu489Lys	missense_variant	9/43	5		ENSP00000488964

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00131 AC: 301 AN: 228944 Hom.: 2 AF XY: 0.00158 AC XY: 199 AN XY: 125674

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.000505

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000566

Gnomad SAS exome AF: 0.00727

Gnomad FIN exome AF: 0.000173

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.000769 AC: 1113 AN: 1448156 Hom.: 6 Cov.: 34 AF XY: 0.000979 AC XY: 704 AN XY: 719134

Gnomad4 AFR exome AF: 0.00363

Gnomad4 AMR exome AF: 0.000566

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00652

Gnomad4 FIN exome AF: 0.0000824

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.000568

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74484

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000495 Hom.: 0

Bravo AF: 0.00126

ESP6500AA AF: 0.00392 AC: 17

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00142 AC: 170

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

FASN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2020

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

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.17
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.077
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.21
MVP		0.36
ClinPred		0.0016	T
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.098
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62642482; hg19: chr17-80049125;