17-82085101-C-T

Variant names:

• chr17-82085101-C-T
• NM_004104.5:c.4343G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004104.5(FASN):​c.4343G>A​(p.Cys1448Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,336 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.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.4343G>A	p.Cys1448Tyr	missense_variant	Exon 25 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.4343G>A	p.Cys1448Tyr	missense_variant	Exon 25 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.4343G>A	p.Cys1448Tyr	missense_variant	Exon 25 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.4337G>A	p.Cys1446Tyr	missense_variant	Exon 25 of 43	5		ENSP00000488964.1
FASN	ENST00000579410.1	n.*57G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 58

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0073	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.25
Sift	Benign	0.20	T;.
Sift4G	Uncertain	0.060	T;T
Polyphen		0.98	D;.
Vest4		0.60
MutPred		0.73		Gain of catalytic residue at L1443 (P = 0.0607);.;
MVP		0.61
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-80042977;