rs2229426

Positions:

• chr17-82083522-G-A
• chr17-82083522-G-C
• chr17-82083522-G-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.5336C>T​(p.Pro1779Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0103 in 1,612,814 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1779A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0086 (9 hom., cov: 34)
  • Exomes 𝑓: 0.010 (79 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.31

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=0.008900583).
• BP6: Variant 17-82083522-G-A is Benign according to our data. Variant chr17-82083522-G-A is described in ClinVar as [Benign]. Clinvar id is 462068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82083522-G-A is described in Lovd as [Likely_benign]. Variant chr17-82083522-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.5336C>T	p.Pro1779Leu	missense_variant	31/43	ENST00000306749.4
FASN	XM_011523538.3	c.5336C>T	p.Pro1779Leu	missense_variant	31/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.5336C>T	p.Pro1779Leu	missense_variant	31/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.5330C>T	p.Pro1777Leu	missense_variant	31/43	5

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1313 AN: 152262 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00856 AC: 2136 AN: 249424 Hom.: 18 AF XY: 0.00853 AC XY: 1155 AN XY: 135466

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00652

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0105 AC: 15309 AN: 1460434 Hom.: 79 Cov.: 37 AF XY: 0.0102 AC XY: 7418 AN XY: 726514

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00853

GnomAD4 genome AF: 0.00862 AC: 1314 AN: 152380 Hom.: 9 Cov.: 34 AF XY: 0.00876 AC XY: 653 AN XY: 74518

Gnomad4 AFR AF: 0.00228

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00925 Hom.: 8

Bravo AF: 0.00713

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00801 AC: 970

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0120

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FASN: BP4, BS1, BS2 -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Benign	0.071
Sift	Benign	0.043	D;.
Sift4G	Uncertain	0.048	D;D
Polyphen		0.033	B;.
Vest4		0.15
MVP		0.30
ClinPred		0.036	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.090
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: rs2229426; hg19: chr17-80041398;