rs2228309

Variant names:

• chr17-82093307-A-G
• rs2228309
• NM_004104.5:c.567T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004104.5(FASN):​c.567T>C​(p.Asn189Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,596,526 control chromosomes in the GnomAD database, including 239,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20291 hom., cov: 34)
  • Exomes 𝑓: 0.54 (218728 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70
• Publications: 33 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=-0.75).
• BP6: Variant 17-82093307-A-G is Benign according to our data. Variant chr17-82093307-A-G is described in ClinVar as Benign. ClinVar VariationId is 1170035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 5 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 5 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 5 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.567T>C	p.Asn189Asn	synonymous_variant	Exon 5 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77245 AN: 152042 Hom.: 20289 Cov.: 34

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.501

GnomAD2 exomes AF: 0.463 AC: 102735 AN: 221732 AF XY: 0.470

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.542 AC: 782135 AN: 1444366 Hom.: 218728 Cov.: 57 AF XY: 0.538 AC XY: 385474 AN XY: 716888

African (AFR) AF: 0.485 AC: 16149 AN: 33330

American (AMR) AF: 0.310 AC: 13055 AN: 42060

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 9973 AN: 25772

East Asian (EAS) AF: 0.144 AC: 5640 AN: 39138

South Asian (SAS) AF: 0.430 AC: 35914 AN: 83490

European-Finnish (FIN) AF: 0.553 AC: 28166 AN: 50894

Middle Eastern (MID) AF: 0.414 AC: 2281 AN: 5506

European-Non Finnish (NFE) AF: 0.580 AC: 640815 AN: 1104382

Other (OTH) AF: 0.504 AC: 30142 AN: 59794

GnomAD4 genome AF: 0.508 AC: 77265 AN: 152160 Hom.: 20291 Cov.: 34 AF XY: 0.502 AC XY: 37342 AN XY: 74388

African (AFR) AF: 0.487 AC: 20242 AN: 41532

American (AMR) AF: 0.408 AC: 6243 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1369 AN: 3462

East Asian (EAS) AF: 0.159 AC: 822 AN: 5172

South Asian (SAS) AF: 0.419 AC: 2026 AN: 4832

European-Finnish (FIN) AF: 0.543 AC: 5756 AN: 10596

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39077 AN: 67952

Other (OTH) AF: 0.496 AC: 1049 AN: 2114

Alfa AF: 0.539 Hom.: 10798

Bravo AF: 0.493

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.2
DANN	Benign	0.29
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228309; hg19: chr17-80051183; COSMIC: COSV60751005; COSMIC: COSV60751005;