rs146800506

Variant names:

• chr17-82086304-G-A
• rs146800506
• NM_004104.5:c.3682C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004104.5(FASN):​c.3682C>T​(p.Leu1228Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,598,490 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (31 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-82086304-G-A is Benign according to our data. Variant chr17-82086304-G-A is described in ClinVar as Benign. ClinVar VariationId is 462042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00918 (1398/152358) while in subpopulation AFR AF = 0.0318 (1323/41590). AF 95% confidence interval is 0.0304. There are 21 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.3682C>T	p.Leu1228Leu	synonymous	Exon 22 of 43	NP_004095.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.3682C>T	p.Leu1228Leu	synonymous	Exon 22 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.3709C>T	p.Leu1237Leu	synonymous	Exon 22 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.3706C>T	p.Leu1236Leu	synonymous	Exon 22 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1397 AN: 152240 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00242 AC: 550 AN: 227150 AF XY: 0.00184

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000698

GnomAD4 exome AF: 0.000981 AC: 1419 AN: 1446132 Hom.: 31 Cov.: 39 AF XY: 0.000856 AC XY: 616 AN XY: 719208

African (AFR) AF: 0.0313 AC: 1044 AN: 33376

American (AMR) AF: 0.00206 AC: 90 AN: 43644

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.000200 AC: 17 AN: 84910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44194

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5694

European-Non Finnish (NFE) AF: 0.0000974 AC: 108 AN: 1109010

Other (OTH) AF: 0.00245 AC: 147 AN: 60022

GnomAD4 genome AF: 0.00918 AC: 1398 AN: 152358 Hom.: 21 Cov.: 33 AF XY: 0.00864 AC XY: 644 AN XY: 74504

African (AFR) AF: 0.0318 AC: 1323 AN: 41590

American (AMR) AF: 0.00287 AC: 44 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00457 Hom.: 3

Bravo AF: 0.0103

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	FASN-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.46
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146800506; hg19: chr17-80044180; COSMIC: COSV100147889; COSMIC: COSV100147889;