17-82081818-G-C

Variant names:

• chr17-82081818-G-C
• rs776553835
• NM_004104.5:c.6189C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004104.5(FASN):​c.6189C>G​(p.Ile2063Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I2063I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.6189C>G	p.Ile2063Met	missense_variant	Exon 37 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.6189C>G	p.Ile2063Met	missense_variant	Exon 37 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.6189C>G	p.Ile2063Met	missense_variant	Exon 37 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.6183C>G	p.Ile2061Met	missense_variant	Exon 37 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		-0.19
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.56
ClinPred		0.99	D
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.70

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: rs776553835; hg19: chr17-80039694;