rs368756460

chr17-82091311-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004104.5(FASN):c.1403G>A(p.Arg468His) variant causes a missense change. The variant allele was found at a frequency of 0.0000714 in 1,610,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R468C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.1403G>A	p.Arg468His	missense_variant	9/43	ENST00000306749.4
FASN	XM_011523538.3	c.1403G>A	p.Arg468His	missense_variant	9/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.1403G>A	p.Arg468His	missense_variant	9/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.1403G>A	p.Arg468His	missense_variant	9/43	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000628 AC: 15 AN: 238864 Hom.: 0 AF XY: 0.0000612 AC XY: 8 AN XY: 130660

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000756

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000699 AC: 102 AN: 1458598 Hom.: 0 Cov.: 34 AF XY: 0.0000606 AC XY: 44 AN XY: 725606

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000801

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.000193

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: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000333 AC: 4

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

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 468 of the FASN protein (p.Arg468His). This variant is present in population databases (rs368756460, gnomAD 0.03%). 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: 569039). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.23
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.38
MVP		0.84
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.82
gMVP		0.76

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: rs368756460; hg19: chr17-80049187;