chr17-82090994-G-A

Position:

• chr17-82090994-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004104.5(FASN):​c.1568C>T​(p.Ser523Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S523S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.1568C>T	p.Ser523Phe	missense_variant	10/43	ENST00000306749.4
FASN	XM_011523538.3	c.1568C>T	p.Ser523Phe	missense_variant	10/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.1568C>T	p.Ser523Phe	missense_variant	10/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.1568C>T	p.Ser523Phe	missense_variant	10/43	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Jan 19, 2024

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 523 of the FASN protein (p.Ser523Phe). This variant is not present in population databases (gnomAD no frequency). 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: 462007). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.68		Loss of disorder (P = 0.0103);Loss of disorder (P = 0.0103);
MVP		0.73
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.81
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1555668714; hg19: chr17-80048870;