rs2229425

Variant names:

• chr17-82083590-G-A
• rs2229425
• NM_004104.5:c.5268C>T

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.5268C>T​(p.Ser1756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,612,004 control chromosomes in the GnomAD database, including 17,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1085 hom., cov: 34)
  • Exomes 𝑓: 0.14 (16467 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0990
• Publications: 14 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=-0.57).
• BP6: Variant 17-82083590-G-A is Benign according to our data. Variant chr17-82083590-G-A is described in ClinVar as Benign. ClinVar VariationId is 1165094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.099 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.5268C>T	p.Ser1756Ser	synonymous	Exon 31 of 43	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.5268C>T	p.Ser1756Ser	synonymous	Exon 31 of 43	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.5262C>T	p.Ser1754Ser	synonymous	Exon 31 of 43	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15491 AN: 152162 Hom.: 1087 Cov.: 34

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.104 AC: 25716 AN: 246688 AF XY: 0.106

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0498

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.141 AC: 206248 AN: 1459724 Hom.: 16467 Cov.: 52 AF XY: 0.139 AC XY: 100712 AN XY: 726070

African (AFR) AF: 0.0211 AC: 707 AN: 33468

American (AMR) AF: 0.0517 AC: 2309 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0511 AC: 1334 AN: 26110

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39680

South Asian (SAS) AF: 0.0503 AC: 4338 AN: 86174

European-Finnish (FIN) AF: 0.151 AC: 7847 AN: 51998

Middle Eastern (MID) AF: 0.0680 AC: 392 AN: 5768

European-Non Finnish (NFE) AF: 0.164 AC: 182273 AN: 1111564

Other (OTH) AF: 0.117 AC: 7042 AN: 60314

GnomAD4 genome AF: 0.102 AC: 15486 AN: 152280 Hom.: 1085 Cov.: 34 AF XY: 0.0998 AC XY: 7432 AN XY: 74458

African (AFR) AF: 0.0273 AC: 1134 AN: 41578

American (AMR) AF: 0.0772 AC: 1182 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0502 AC: 242 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1602 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10854 AN: 67992

Other (OTH) AF: 0.0974 AC: 206 AN: 2116

Alfa AF: 0.131 Hom.: 2141

Bravo AF: 0.0925

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		-0.099
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	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: rs2229425; hg19: chr17-80041466; COSMIC: COSV60754856; COSMIC: COSV60754856;