17-82082158-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004104.5(FASN):c.6014T>C(p.Val2005Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 1,602,730 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2005G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 113 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 253 hom. )

Consequence

FASN
NM_004104.5 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.40

Publications

11 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

new If you want to explore the variant's impact on the transcript NM_004104.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028517246).

BP6

Variant 17-82082158-A-G is Benign according to our data. Variant chr17-82082158-A-G is described in ClinVar as Benign. ClinVar VariationId is 462088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.6014T>C	p.Val2005Ala	missense splice_region	Exon 36 of 43	NP_004095.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASN	ENST00000306749.4	TSL:1 MANE Select	c.6014T>C	p.Val2005Ala	missense splice_region	Exon 36 of 43	ENSP00000304592.2	P49327
FASN	ENST00000940344.1		c.6041T>C	p.Val2014Ala	missense splice_region	Exon 36 of 43	ENSP00000610403.1
FASN	ENST00000940346.1		c.6038T>C	p.Val2013Ala	missense splice_region	Exon 36 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3680

AN:

152108

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0692

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.0133

Gnomad SAS

AF:

0.0524

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.0240

GnomAD2 exomes

AF:

0.0147

AC:

3562

AN:

241562

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.0725

Gnomad AMR exome

AF:

0.00777

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.0117

Gnomad FIN exome

AF:

0.0000707

Gnomad NFE exome

AF:

0.00206

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00725

AC:

10515

AN:

1450506

Hom.:

253

Cov.:

AF XY:

0.00800

AC XY:

5778

AN XY:

721876

show subpopulations

African (AFR)

AF:

0.0730

AC:

2444

AN:

33470

American (AMR)

AF:

0.00890

AC:

398

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

533

AN:

26134

East Asian (EAS)

AF:

0.0135

AC:

535

AN:

39694

South Asian (SAS)

AF:

0.0435

AC:

3749

AN:

86254

European-Finnish (FIN)

AF:

0.0000237

AC:

AN:

42266

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00175

AC:

1951

AN:

1111904

Other (OTH)

AF:

0.0136

AC:

820

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

650

1301

1951

2602

3252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.0243

AC:

3699

AN:

152224

Hom.:

113

Cov.:

AF XY:

0.0244

AC XY:

1813

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0692

AC:

2872

AN:

41524

American (AMR)

AF:

0.0145

AC:

222

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3468

East Asian (EAS)

AF:

0.0133

AC:

AN:

5190

South Asian (SAS)

AF:

0.0521

AC:

251

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68000

Other (OTH)

AF:

0.0313

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0120

Hom.:

104

Bravo

AF:

0.0262

Asia WGS

AF:

0.0660

AC:

228

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.25

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.70

PhyloP100

3.4

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

REVEL

Benign

0.069

Sift

Benign

0.80

Sift4G

Benign

0.81

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.20

gMVP

0.44

Mutation Taster

=63/37

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over