rs142371324

Positions:

• chr17-82088005-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004104.5(FASN):​c.2815G>A​(p.Glu939Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,612,758 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (45 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071086884).
• BP6: Variant 17-82088005-C-T is Benign according to our data. Variant chr17-82088005-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 462030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 831 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.2815G>A	p.Glu939Lys	missense_variant	18/43	ENST00000306749.4
FASN	XM_011523538.3	c.2815G>A	p.Glu939Lys	missense_variant	18/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.2815G>A	p.Glu939Lys	missense_variant	18/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.2815G>A	p.Glu939Lys	missense_variant	18/43	5

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 831 AN: 152166 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00553 AC: 1379 AN: 249508 Hom.: 15 AF XY: 0.00558 AC XY: 757 AN XY: 135564

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00467 AC: 6819 AN: 1460472 Hom.: 45 Cov.: 35 AF XY: 0.00463 AC XY: 3365 AN XY: 726530

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152286 Hom.: 8 Cov.: 33 AF XY: 0.00682 AC XY: 508 AN XY: 74452

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.00518

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00509 Hom.: 0

Bravo AF: 0.00288

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00490 AC: 594

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

FASN: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.054
Sift	Benign	0.35	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.0020	B;.
Vest4		0.46
MVP		0.30
ClinPred		0.012	T
GERP RS		-0.85
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.083
gMVP		0.64

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

Other links and lift over

dbSNP: rs142371324; hg19: chr17-80045881; COSMIC: COSV100148570; COSMIC: COSV100148570;