17-82084092-C-G

Variant names:

• chr17-82084092-C-G
• rs369709982
• NM_004104.5:c.4981G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004104.5(FASN):​c.4981G>C​(p.Val1661Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,412,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign 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. V1661M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FASN NM_004104.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

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]

FASN Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5	c.4981G>C	p.Val1661Leu	missense_variant	Exon 29 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3	c.4981G>C	p.Val1661Leu	missense_variant	Exon 29 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4	c.4981G>C	p.Val1661Leu	missense_variant	Exon 29 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1	c.4975G>C	p.Val1659Leu	missense_variant	Exon 29 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412952 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 698788

African (AFR) AF: 0.00 AC: 0 AN: 32134

American (AMR) AF: 0.00 AC: 0 AN: 37322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 36598

South Asian (SAS) AF: 0.00 AC: 0 AN: 80700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088490

Other (OTH) AF: 0.00 AC: 0 AN: 58604

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.039
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;.
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.14
Sift	Benign	0.092	T;.
Sift4G	Benign	0.085	T;T
Polyphen		0.28	B;.
Vest4		0.62
MutPred		0.45		Loss of methylation at R1664 (P = 0.1108);.;
MVP		0.40
ClinPred		0.71	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.84

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

Other links and lift over

dbSNP: rs369709982; hg19: chr17-80041968;