rs756441396

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000306749.4(FASN):​c.1118G>A​(p.Arg373Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,590,170 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R373R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

FASN
ENST00000306749.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.81
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41355756).
BS2
High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FASNNM_004104.5 linkuse as main transcriptc.1118G>A p.Arg373Gln missense_variant 9/43 ENST00000306749.4 NP_004095.4
FASNXM_011523538.3 linkuse as main transcriptc.1118G>A p.Arg373Gln missense_variant 9/43 XP_011521840.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FASNENST00000306749.4 linkuse as main transcriptc.1118G>A p.Arg373Gln missense_variant 9/431 NM_004104.5 ENSP00000304592 P1
FASNENST00000634990.1 linkuse as main transcriptc.1118G>A p.Arg373Gln missense_variant 9/435 ENSP00000488964

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000245
AC:
5
AN:
204190
Hom.:
0
AF XY:
0.0000452
AC XY:
5
AN XY:
110672
show subpopulations
Gnomad AFR exome
AF:
0.0000814
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000758
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000112
Gnomad OTH exome
AF:
0.000194
GnomAD4 exome
AF:
0.0000153
AC:
22
AN:
1437978
Hom.:
1
Cov.:
35
AF XY:
0.0000210
AC XY:
15
AN XY:
713032
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.0000248
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000967
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000726
Gnomad4 OTH exome
AF:
0.0000336
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
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:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000251
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2022The c.1118G>A (p.R373Q) alteration is located in exon 9 (coding exon 8) of the FASN gene. This alteration results from a G to A substitution at nucleotide position 1118, causing the arginine (R) at amino acid position 373 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 13, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 373 of the FASN protein (p.Arg373Gln). This variant is present in population databases (rs756441396, gnomAD 0.009%). 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: 574406). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
0.066
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;.
Eigen
Benign
0.073
Eigen_PC
Benign
-0.040
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.41
T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
0.97
D
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-2.2
N;.
REVEL
Benign
0.20
Sift
Benign
0.069
T;.
Sift4G
Benign
0.067
T;D
Polyphen
1.0
D;.
Vest4
0.27
MutPred
0.53
Loss of catalytic residue at R373 (P = 0.1301);Loss of catalytic residue at R373 (P = 0.1301);
MVP
0.46
ClinPred
0.18
T
GERP RS
1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.11
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs756441396; hg19: chr17-80049472; API