Genetic Variant FASN:p.Ser2221Cys (chr17-82080856-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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. 15/22 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. S2221F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.726

Publications

0 publications found

Variant links:

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

FASN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
FASN	NM_004104.5 link	c.6662C>G	p.Ser2221Cys	missense_variant	Exon 39 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3 link	c.6662C>G	p.Ser2221Cys	missense_variant	Exon 39 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FASN	ENST00000306749.4 link	c.6662C>G	p.Ser2221Cys	missense_variant	Exon 39 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1 link	c.6656C>G	p.Ser2219Cys	missense_variant	Exon 39 of 43	5		ENSP00000488964.1
FASN	ENST00000578424.2 link	n.-161C>G		upstream_gene_variant		2
FASN	ENST00000580382.1 link	n.-116C>G		upstream_gene_variant		3		ENSP00000462949.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000818

AC:

AN:

244452

AF XY:

0.00000752

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459256

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111600

Other (OTH)

AF:

0.00

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.

PhyloP100

0.73

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.055

Sift

Benign

0.053

T;.

Sift4G

Uncertain

0.053

T;T

Vest4

0.24

ClinPred

0.11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over