rs758520407

Positions:

• chr17-82080694-C-A
• chr17-82080694-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004104.5(FASN):​c.6824G>T​(p.Arg2275Leu) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2275Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FASN NM_004104.5 missense, splice_region
• Scores: Splicing: ADA: 0.0005529
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.583

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15647942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.6824G>T	p.Arg2275Leu	missense_variant, splice_region_variant	39/43	ENST00000306749.4
FASN	XM_011523538.3	c.6824G>T	p.Arg2275Leu	missense_variant, splice_region_variant	39/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.6824G>T	p.Arg2275Leu	missense_variant, splice_region_variant	39/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.6818G>T	p.Arg2273Leu	missense_variant, splice_region_variant	39/43	5
FASN	ENST00000578424.2	n.2G>T		non_coding_transcript_exon_variant	1/4	2
FASN	ENST00000580382.1	c.50G>T	p.Arg17Leu	missense_variant, splice_region_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000970 AC: 2 AN: 206272 Hom.: 0 AF XY: 0.00000901 AC XY: 1 AN XY: 110984

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: 0.0000381

Gnomad FIN exome AF: 0.0000569

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1434290 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 710782

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.88	N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Benign	0.029
Sift	Benign	0.16	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.71	P;.
Vest4		0.27
MutPred		0.49		Loss of solvent accessibility (P = 0.0098);.;
MVP		0.40
ClinPred		0.95	D
GERP RS		0.098
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.030		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: rs758520407; hg19: chr17-80038570;