dbSNP rs62642482: FASN:p.Glu489Lys (chr17-82091249-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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. 16/22 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

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.467

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 462005.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

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.1465G>A	p.Glu489Lys	missense	Exon 9 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.1465G>A	p.Glu489Lys	missense	Exon 9 of 43	ENSP00000304592.2	P49327
FASN	ENST00000940344.1		c.1492G>A	p.Glu498Lys	missense	Exon 9 of 43	ENSP00000610403.1
FASN	ENST00000940346.1		c.1465G>A	p.Glu489Lys	missense	Exon 9 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

152208

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00131

AC:

301

AN:

228944

AF XY:

0.00158

show subpopulations

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 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.:

Cov.:

AF XY:

0.000979

AC XY:

704

AN XY:

719134

show subpopulations

African (AFR)

AF:

0.00363

AC:

121

AN:

33300

American (AMR)

AF:

0.000566

AC:

AN:

44172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25724

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39366

South Asian (SAS)

AF:

0.00652

AC:

556

AN:

85318

European-Finnish (FIN)

AF:

0.0000824

AC:

AN:

48558

Middle Eastern (MID)

AF:

0.000873

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000331

AC:

366

AN:

1106152

Other (OTH)

AF:

0.000568

AC:

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00139

AC:

211

AN:

152326

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00358

AC:

149

AN:

41572

American (AMR)

AF:

0.000784

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00518

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000561

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00392

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00142

AC:

170

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

FASN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.17

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.23

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.50

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.3

PhyloP100

-0.47

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.16

REVEL

Benign

0.077

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.21

MVP

0.36

ClinPred

0.0016

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.098

gMVP

0.37

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over