Genetic Variant FASN:p.Glu1485Asp (chr17-82084908-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004104.5(FASN):c.4455G>C(p.Glu1485Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E1485E) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.899

Publications

0 publications found

Variant links:

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]

FASN Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

FASN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03420648).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. 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
	FASN	NM_004104.5	MANE Select	c.4455G>C	p.Glu1485Asp	missense	Exon 26 of 43	NP_004095.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASN	ENST00000306749.4	TSL:1 MANE Select	c.4455G>C	p.Glu1485Asp	missense	Exon 26 of 43	ENSP00000304592.2	P49327
FASN	ENST00000940344.1		c.4482G>C	p.Glu1494Asp	missense	Exon 26 of 43	ENSP00000610403.1
FASN	ENST00000940346.1		c.4479G>C	p.Glu1493Asp	missense	Exon 26 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399774

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31746

American (AMR)

AF:

0.0000279

AC:

AN:

35842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

35898

South Asian (SAS)

AF:

0.00

AC:

AN:

79472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079780

Other (OTH)

AF:

0.00

AC:

AN:

58042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.11

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.25

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.47

M_CAP

Benign

0.0038

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.56

PhyloP100

-0.90

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.030

REVEL

Benign

0.0010

Sift

Benign

0.71

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.062

MutPred

0.21

Gain of helix (P = 0.0078)

MVP

0.25

ClinPred

0.023

GERP RS

-4.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.2

Varity_R

0.082

gMVP

0.20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over