dbSNP rs758520407: FASN:p.Arg2275Leu (chr17-82080694-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004104.5(FASN):c.6824G>T(p.Arg2275Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R2275Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FASN
NM_004104.5 missense, splice_region

Scores

Splicing: ADA: 0.0005529

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.583

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15647942).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.6824G>T	p.Arg2275Leu	missense splice_region	Exon 39 of 43	NP_004095.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FASN	ENST00000306749.4	TSL:1 MANE Select	c.6824G>T	p.Arg2275Leu	missense splice_region	Exon 39 of 43	ENSP00000304592.2
FASN	ENST00000634990.1	TSL:5	c.6818G>T	p.Arg2273Leu	missense splice_region	Exon 39 of 43	ENSP00000488964.1
FASN	ENST00000578424.2	TSL:2	n.2G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000970

AC:

AN:

206272

AF XY:

0.00000901

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:

0.0000569

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1434290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710782

African (AFR)

AF:

0.00

AC:

AN:

33236

American (AMR)

AF:

0.00

AC:

AN:

39738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25544

East Asian (EAS)

AF:

0.00

AC:

AN:

38626

South Asian (SAS)

AF:

0.00

AC:

AN:

82426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099508

Other (OTH)

AF:

0.00

AC:

AN:

59372

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0089

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

0.58

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.029

Sift

Benign

0.16

Sift4G

Benign

0.21

Polyphen

0.71

Vest4

0.27

MutPred

0.49

Loss of solvent accessibility (P = 0.0098)

MVP

0.40

ClinPred

0.95

GERP RS

0.098

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00055

dbscSNV1_RF

Benign

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over