chr17-82088251-C-A

Position:

• chr17-82088251-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004104.5(FASN):​c.2650G>T​(p.Val884Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V884I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASN	NM_004104.5	c.2650G>T	p.Val884Phe	missense_variant	17/43	ENST00000306749.4
FASN	XM_011523538.3	c.2650G>T	p.Val884Phe	missense_variant	17/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASN	ENST00000306749.4	c.2650G>T	p.Val884Phe	missense_variant	17/43	1	NM_004104.5	P1
FASN	ENST00000634990.1	c.2650G>T	p.Val884Phe	missense_variant	17/43	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243222 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132644

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: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454928 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 724024

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.40		Loss of catalytic residue at V884 (P = 0.0411);Loss of catalytic residue at V884 (P = 0.0411);
MVP		0.90
ClinPred		0.65	D
GERP RS		0.98
Varity_R		0.46
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs750385551; hg19: chr17-80046127;