17-82084587-G-T

Position:

• chr17-82084587-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_004104.5(FASN):​c.4694C>A​(p.Thr1565Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

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_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071635485).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.4694C>A	p.Thr1565Lys	missense_variant	27/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.4694C>A	p.Thr1565Lys	missense_variant	27/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.4694C>A	p.Thr1565Lys	missense_variant	27/43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.4688C>A	p.Thr1563Lys	missense_variant	27/43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458404 Hom.: 0 Cov.: 42 AF XY: 0.00000552 AC XY: 4 AN XY: 725248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.65	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.054
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.23
MutPred		0.55		Gain of methylation at T1565 (P = 0.0127);.;
MVP		0.27
ClinPred		0.14	T
GERP RS		0.85
Varity_R		0.17
gMVP		0.51

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: rs1294023345; hg19: chr17-80042463;