rs2228307

Variant names:

• chr17-82083019-T-C
• rs2228307
• NM_004104.5:c.5662A>G
• FASN p.Ile1888Val

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004104.5(FASN):​c.5662A>G​(p.Ile1888Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,612,872 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (150 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (169 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0370
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032187104).
• BP6: Variant 17-82083019-T-C is Benign according to our data. Variant chr17-82083019-T-C is described in ClinVar as Benign. ClinVar VariationId is 462079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0893 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.5662A>G	p.Ile1888Val	missense	Exon 33 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.5662A>G	p.Ile1888Val	missense	Exon 33 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.5689A>G	p.Ile1897Val	missense	Exon 33 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.5686A>G	p.Ile1896Val	missense	Exon 33 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3987 AN: 152096 Hom.: 146 Cov.: 33

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00715 AC: 1789 AN: 250062 AF XY: 0.00516

Gnomad AFR exome AF: 0.0962

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00276 AC: 4030 AN: 1460658 Hom.: 169 Cov.: 36 AF XY: 0.00249 AC XY: 1810 AN XY: 726626

African (AFR) AF: 0.0963 AC: 3225 AN: 33478

American (AMR) AF: 0.00572 AC: 256 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52250

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 125 AN: 1111980

Other (OTH) AF: 0.00641 AC: 387 AN: 60376

GnomAD4 genome AF: 0.0264 AC: 4017 AN: 152214 Hom.: 150 Cov.: 33 AF XY: 0.0254 AC XY: 1891 AN XY: 74432

African (AFR) AF: 0.0917 AC: 3807 AN: 41514

American (AMR) AF: 0.0107 AC: 163 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68000

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0121 Hom.: 127

Bravo AF: 0.0302

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.021
DANN	Benign	0.29
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N
PhyloP100		0.037
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.044
Sift	Benign	0.53	T
Sift4G	Benign	0.52	T
Varity_R		0.048
gMVP		0.39
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2228307;

hg19: chr17-80040895;

COSMIC: COSV60763024;

COSMIC: COSV60763024;