Genetic Variant FASN:p.Val376Leu (chr17-82091588-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004104.5(FASN):c.1126G>C(p.Val376Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000627 in 1,436,386 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

FASN
NM_004104.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.89

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 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 link	c.1126G>C	p.Val376Leu	missense_variant	Exon 9 of 43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3 link	c.1126G>C	p.Val376Leu	missense_variant	Exon 9 of 43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 link	c.1126G>C	p.Val376Leu	missense_variant	Exon 9 of 43	1	NM_004104.5	ENSP00000304592.2
FASN	ENST00000634990.1 link	c.1126G>C	p.Val376Leu	missense_variant	Exon 9 of 43	5		ENSP00000488964.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000496

AC:

AN:

201540

AF XY:

0.00000916

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:

0.00

Gnomad OTH exome

AF:

0.000195

GnomAD4 exome

AF:

0.00000627

AC:

AN:

1436386

Hom.:

Cov.:

AF XY:

0.00000702

AC XY:

AN XY:

712216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

40016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25568

East Asian (EAS)

AF:

0.00

AC:

AN:

38592

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000726

AC:

AN:

1101378

Other (OTH)

AF:

0.00

AC:

AN:

59486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

Cov.:

Alfa

AF:

0.0000508

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000839

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

4.9

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

N;.

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.69

MutPred

0.68

Gain of loop (P = 0.2754);Gain of loop (P = 0.2754);

MVP

0.44

ClinPred

0.91

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.81

gMVP

0.75

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over