dbSNP rs534878599: FASN:p.Arg1705Leu (chr17-82083876-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004104.5(FASN):c.5114G>T(p.Arg1705Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,740 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. R1705W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5 link	c.5114G>T	p.Arg1705Leu	missense_variant	Exon 30 of 43	ENST00000306749.4	NP_004095.4	P49327
FASN	XM_011523538.3 link	c.5114G>T	p.Arg1705Leu	missense_variant	Exon 30 of 43		XP_011521840.1	P49327

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 link	c.5114G>T	p.Arg1705Leu	missense_variant	Exon 30 of 43	1	NM_004104.5	ENSP00000304592.2		P49327
FASN	ENST00000634990.1 link	c.5108G>T	p.Arg1703Leu	missense_variant	Exon 30 of 43	5		ENSP00000488964.1		A0A0U1RQF0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419740

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702010

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33048

American (AMR)

AF:

0.00

AC:

AN:

37350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25316

East Asian (EAS)

AF:

0.00

AC:

AN:

38242

South Asian (SAS)

AF:

0.00

AC:

AN:

81054

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090740

Other (OTH)

AF:

0.00

AC:

AN:

58936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.

PhyloP100

1.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Benign

0.12

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.44

B;.

Vest4

0.66

MutPred

0.64

Loss of MoRF binding (P = 0.0483);.;

MVP

0.42

ClinPred

0.99

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.82

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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