rs540009159

chr17-82088428-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004104.5(FASN):c.2555A>G(p.Asn852Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N852D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009908795).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.2555A>G	p.Asn852Ser	missense_variant	16/43	ENST00000306749.4
FASN	XM_011523538.3	c.2555A>G	p.Asn852Ser	missense_variant	16/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.2555A>G	p.Asn852Ser	missense_variant	16/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.2555A>G	p.Asn852Ser	missense_variant	16/43	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000362 AC: 9 AN: 248354 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135138

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1459688 Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13 AN XY: 725970

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74390

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000997 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 579057). This variant has not been reported in the literature in individuals affected with FASN-related conditions. This variant is present in population databases (rs540009159, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 852 of the FASN protein (p.Asn852Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.026
Dann	Benign	0.71
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0099	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.10	N;.
REVEL	Benign	0.014
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.076
MVP		0.29
ClinPred		0.0072	T
GERP RS		-0.72
Varity_R		0.077
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs540009159; hg19: chr17-80046304; COSMIC: COSV60761238; COSMIC: COSV60761238;