rs2228305

Variant names:

• chr17-82084916-C-G
• rs2228305
• NM_004104.5:c.4447G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-82084916-C-G
• chr17-82084916-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004104.5(FASN):​c.4447G>C​(p.Val1483Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1483I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08021355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.4447G>C	p.Val1483Leu	missense_variant	Exon 26 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.4447G>C	p.Val1483Leu	missense_variant	Exon 26 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.4447G>C	p.Val1483Leu	missense_variant	Exon 26 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.4441G>C	p.Val1481Leu	missense_variant	Exon 26 of 43	5		ENSP00000488964.1
FASN	ENST00000579410.1	n.*242G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FASN: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.070
DANN	Benign	0.81
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		-1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.22	N;.
REVEL	Benign	0.011
Sift	Benign	0.34	T;.
Sift4G	Benign	0.64	T;T
Polyphen		0.010	B;.
Vest4		0.16
MutPred		0.12		Gain of disorder (P = 0.2007);.;
MVP		0.32
ClinPred		0.084	T
GERP RS		-1.7
Varity_R		0.11
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2228305; hg19: chr17-80042792;