rs142734133

Positions:

• chr17-82092946-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.729C>T​(p.Tyr243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,609,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.55

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 17-82092946-G-A is Benign according to our data. Variant chr17-82092946-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BS2: High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.729C>T	p.Tyr243=	synonymous_variant	6/43	ENST00000306749.4
FASN	XM_011523538.3	c.729C>T	p.Tyr243=	synonymous_variant	6/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.729C>T	p.Tyr243=	synonymous_variant	6/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.729C>T	p.Tyr243=	synonymous_variant	6/43	5

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000232 AC: 56 AN: 241312 Hom.: 0 AF XY: 0.000221 AC XY: 29 AN XY: 131322

Gnomad AFR exome AF: 0.000660

Gnomad AMR exome AF: 0.000677

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000556

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000137 AC: 199 AN: 1457494 Hom.: 0 Cov.: 36 AF XY: 0.000130 AC XY: 94 AN XY: 724752

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000698

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000918

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74472

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000748

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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). -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.040
DANN	Benign	0.71

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: rs142734133; hg19: chr17-80050822;