rs2228307

Positions:

• chr17-82083019-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.5662A>G	p.Ile1888Val	missense_variant	33/43	ENST00000306749.4
FASN	XM_011523538.3	c.5662A>G	p.Ile1888Val	missense_variant	33/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.5662A>G	p.Ile1888Val	missense_variant	33/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.5656A>G	p.Ile1886Val	missense_variant	33/43	5

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

GnomAD3 exomes AF: 0.00715 AC: 1789 AN: 250062 Hom.: 78 AF XY: 0.00516 AC XY: 700 AN XY: 135702

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 SAS exome AF: 0.000163

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

Gnomad4 AFR exome AF: 0.0963

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00641

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

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00643 Hom.: 40

Bravo AF: 0.0302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0873 AC: 384

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00871 AC: 1056

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N;.
REVEL	Benign	0.044
Sift	Benign	0.53	T;.
Sift4G	Benign	0.52	T;T
Polyphen		0.0050	B;.
Vest4		0.099
MVP		0.23
ClinPred		0.0025	T
GERP RS		-8.2
Varity_R		0.048
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228307; hg19: chr17-80040895; COSMIC: COSV60763024; COSMIC: COSV60763024;