rs764159372

chr17-82085775-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004104.5(FASN):c.3829C>G(p.Pro1277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,561,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1277R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.236

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]

FASN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056882203).

BP6

Variant 17-82085775-G-C is Benign according to our data. Variant chr17-82085775-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462045.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5 linkuse as main transcript	c.3829C>G	p.Pro1277Ala	missense_variant	23/43	ENST00000306749.4
FASN	XM_011523538.3 linkuse as main transcript	c.3829C>G	p.Pro1277Ala	missense_variant	23/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4 linkuse as main transcript	c.3829C>G	p.Pro1277Ala	missense_variant	23/43	1	NM_004104.5	P1
FASN	ENST00000634990.1 linkuse as main transcript	c.3823C>G	p.Pro1275Ala	missense_variant	23/43	5

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

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:

0.00152

AC:

253

AN:

166848

Hom.:

AF XY:

0.00117

AC XY:

106

AN XY:

90698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00937

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000877

GnomAD4 exome

AF:

0.000216

AC:

304

AN:

1409078

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

125

AN XY:

695702

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.00792

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.21e-7

Gnomad4 OTH exome

AF:

0.0000514

GnomAD4 genome

AF:

0.000217

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00216

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:

0.000260

Hom.:

Bravo

AF:

0.000608

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 21, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (33/15288) (https://gnomad.broadinstitute.org/variant/17-82085775-G-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:462045). This variant amino acid Alanine (Ala) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

FASN-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

Cadd

Benign

0.22

Dann

Benign

0.45

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.79

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.1

N;.

REVEL

Benign

0.086

Sift

Benign

0.49

T;.

Sift4G

Benign

0.78

T;T

Polyphen

0.0010

B;.

Vest4

0.15

MutPred

0.59

Loss of disorder (P = 0.1195);.;

MVP

0.26

ClinPred

0.015

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Varity_R

0.074

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over