rs143618212

chr17-82092981-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004104.5(FASN):c.694C>T(p.Leu232=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,612,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.953

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-82092981-G-A is Benign according to our data. Variant chr17-82092981-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82092981-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.953 with no splicing effect.
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.694C>T	p.Leu232=	synonymous_variant	6/43	ENST00000306749.4
FASN	XM_011523538.3	c.694C>T	p.Leu232=	synonymous_variant	6/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.694C>T	p.Leu232=	synonymous_variant	6/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.694C>T	p.Leu232=	synonymous_variant	6/43	5

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000612 AC: 151 AN: 246890 Hom.: 1 AF XY: 0.000729 AC XY: 98 AN XY: 134408

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000711

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000479 AC: 699 AN: 1459884 Hom.: 1 Cov.: 36 AF XY: 0.000511 AC XY: 371 AN XY: 726178

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000363

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000949

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

FASN-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

This 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

FASN: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	3.0
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143618212; hg19: chr17-80050857;