rs377037839

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004104.5(FASN):c.4996C>T(p.Arg1666Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,554,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1666H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16843131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5 link	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43	ENST00000306749.4	NP_004095.4	P49327
FASN	XM_011523538.3 link	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43		XP_011521840.1	P49327

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 link	c.4996C>T	p.Arg1666Cys	missense_variant	Exon 29 of 43	1	NM_004104.5	ENSP00000304592.2		P49327
FASN	ENST00000634990.1 link	c.4990C>T	p.Arg1664Cys	missense_variant	Exon 29 of 43	5		ENSP00000488964.1		A0A0U1RQF0

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000150

AC:

AN:

153010

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.0000793

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000897

Gnomad FIN exome

AF:

0.0000723

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000528

AC:

AN:

1402650

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

692786

show subpopulations

African (AFR)

AF:

0.000157

AC:

AN:

31854

American (AMR)

AF:

0.0000550

AC:

AN:

36368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.0000554

AC:

AN:

36084

South Asian (SAS)

AF:

0.000701

AC:

AN:

79868

European-Finnish (FIN)

AF:

0.0000217

AC:

AN:

46160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000462

AC:

AN:

1083142

Other (OTH)

AF:

0.0000515

AC:

AN:

58244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000888

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1666 of the FASN protein (p.Arg1666Cys). This variant is present in population databases (rs377037839, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FASN-related conditions. ClinVar contains an entry for this variant (Variation ID: 531054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

2.4

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Benign

0.086

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.49

MVP

0.44

ClinPred

0.14

GERP RS

2.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.23

gMVP

0.71

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over