rs2228306

Positions:

• chr17-82082158-A-C
• chr17-82082158-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004104.5(FASN):​c.6014T>G​(p.Val2005Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. V2005A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FASN NM_004104.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6014T>G	p.Val2005Gly	missense_variant, splice_region_variant	36/43	ENST00000306749.4
FASN	XM_011523538.3	c.6014T>G	p.Val2005Gly	missense_variant, splice_region_variant	36/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6014T>G	p.Val2005Gly	missense_variant, splice_region_variant	36/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6008T>G	p.Val2003Gly	missense_variant, splice_region_variant	36/43	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

ClinVar contains an entry for this variant (Variation ID: 858510). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FASN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2005 of the FASN protein (p.Val2005Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	8.8e-15	P
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.069	T;D
Polyphen		0.66	P;.
Vest4		0.59
MutPred		0.83		Loss of stability (P = 7e-04);.;
MVP		0.76
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228306; hg19: chr17-80040034;