17-82080856-G-C

Position:

• chr17-82080856-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004104.5(FASN):​c.6662C>G​(p.Ser2221Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.726

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27156132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5	c.6662C>G	p.Ser2221Cys	missense_variant	39/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.6662C>G	p.Ser2221Cys	missense_variant	39/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.6662C>G	p.Ser2221Cys	missense_variant	39/43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.6656C>G	p.Ser2219Cys	missense_variant	39/43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000818 AC: 2 AN: 244452 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 133064

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459256 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725838

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.055
Sift	Benign	0.053	T;.
Sift4G	Uncertain	0.053	T;T
Polyphen		0.72	P;.
Vest4		0.24
MutPred		0.42		Gain of catalytic residue at L2222 (P = 0.011);.;
MVP		0.43
ClinPred		0.11	T
GERP RS		1.1
Varity_R		0.10
gMVP		0.51

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: rs774233186; hg19: chr17-80038732;