Genetic Variant FASN:p.Asp1508Glu (chr17-82084839-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004104.5(FASN):c.4524C>G(p.Asp1508Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1508N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.338

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3942911).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.4524C>G	p.Asp1508Glu	missense	Exon 26 of 43	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.4524C>G	p.Asp1508Glu	missense	Exon 26 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.4518C>G	p.Asp1506Glu	missense	Exon 26 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398076

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689556

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31602

American (AMR)

AF:

0.00

AC:

AN:

35730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47950

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078948

Other (OTH)

AF:

0.00

AC:

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.5

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.010

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

-0.34

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.13

Sift

Uncertain

0.010

Sift4G

Benign

0.067

Polyphen

1.0

Vest4

0.46

MutPred

0.51

Loss of sheet (P = 0.0817)

MVP

0.59

ClinPred

0.99

GERP RS

-3.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.42

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over