rs562846615

Variant summary

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

The NM_004104.5(FASN):​c.820C>T​(p.Arg274Cys) 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 1,605,468 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.0930
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]

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=0.16442424).
BS2
High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FASNNM_004104.5 linkuse as main transcriptc.820C>T p.Arg274Cys missense_variant 7/43 ENST00000306749.4 NP_004095.4 P49327
FASNXM_011523538.3 linkuse as main transcriptc.820C>T p.Arg274Cys missense_variant 7/43 XP_011521840.1 P49327

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FASNENST00000306749.4 linkuse as main transcriptc.820C>T p.Arg274Cys missense_variant 7/431 NM_004104.5 ENSP00000304592.2 P49327
FASNENST00000634990.1 linkuse as main transcriptc.820C>T p.Arg274Cys missense_variant 7/435 ENSP00000488964.1 A0A0U1RQF0

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152098
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000467
AC:
11
AN:
235568
Hom.:
0
AF XY:
0.0000468
AC XY:
6
AN XY:
128154
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000297
Gnomad ASJ exome
AF:
0.000103
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000172
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000283
Gnomad OTH exome
AF:
0.000173
GnomAD4 exome
AF:
0.0000337
AC:
49
AN:
1453252
Hom.:
0
Cov.:
36
AF XY:
0.0000401
AC XY:
29
AN XY:
722388
show subpopulations
Gnomad4 AFR exome
AF:
0.0000600
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.000129
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000666
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000582
AC:
7
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2023In 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine 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: 531031). This variant has not been reported in the literature in individuals affected with FASN-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 274 of the FASN protein (p.Arg274Cys). -
FASN-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 22, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.86
D;.
Eigen
Benign
-0.98
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.66
T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Pathogenic
3.0
M;.
PrimateAI
Benign
0.27
T
PROVEAN
Uncertain
-4.1
D;.
REVEL
Benign
0.062
Sift
Benign
0.096
T;.
Sift4G
Uncertain
0.038
D;D
Polyphen
0.10
B;.
Vest4
0.42
MutPred
0.70
Loss of disorder (P = 0.0837);Loss of disorder (P = 0.0837);
MVP
0.35
ClinPred
0.13
T
GERP RS
-2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs562846615; hg19: chr17-80050647; API