rs377076774

Positions:

chr17-82092755-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004104.5(FASN):c.836C>T(p.Ser279Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07029712).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5 linkuse as main transcript	c.836C>T	p.Ser279Leu	missense_variant	7/43	ENST00000306749.4	NP_004095.4	P49327
FASN	XM_011523538.3 linkuse as main transcript	c.836C>T	p.Ser279Leu	missense_variant	7/43		XP_011521840.1	P49327

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 linkuse as main transcript	c.836C>T	p.Ser279Leu	missense_variant	7/43	1	NM_004104.5	ENSP00000304592.2		P49327
FASN	ENST00000634990.1 linkuse as main transcript	c.836C>T	p.Ser279Leu	missense_variant	7/43	5		ENSP00000488964.1		A0A0U1RQF0

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

237932

Hom.:

AF XY:

0.0000849

AC XY:

AN XY:

129562

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000323

AC:

AN:

1453838

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

722876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000452

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.0000586

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000997

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 279 of the FASN protein (p.Ser279Leu). This variant is present in population databases (rs377076774, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FASN-related conditions. ClinVar contains an entry for this variant (Variation ID: 573182). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.836C>T (p.S279L) alteration is located in exon 7 (coding exon 6) of the FASN gene. This alteration results from a C to T substitution at nucleotide position 836, causing the serine (S) at amino acid position 279 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.070

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.67

N;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.047

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.59

P;.

Vest4

0.37

MVP

0.12

ClinPred

0.059

GERP RS

1.3

Varity_R

0.20

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over