chr17-82081205-C-T

Position:

chr17-82081205-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000306749.4(FASN):c.6554G>A(p.Arg2185Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,594,278 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2185W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0079 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 16 hom. )

Consequence

FASN
ENST00000306749.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.03

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048415065).

BP6

Variant 17-82081205-C-T is Benign according to our data. Variant chr17-82081205-C-T is described in ClinVar as [Benign]. Clinvar id is 462102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82081205-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00786 (1197/152334) while in subpopulation AFR AF= 0.0273 (1137/41580). AF 95% confidence interval is 0.026. There are 12 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1197 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASN	NM_004104.5 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	38/43	ENST00000306749.4	NP_004095.4
FASN	XM_011523538.3 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	38/43		XP_011521840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 linkuse as main transcript	c.6554G>A	p.Arg2185Gln	missense_variant	38/43	1	NM_004104.5	ENSP00000304592	P1
FASN	ENST00000634990.1 linkuse as main transcript	c.6548G>A	p.Arg2183Gln	missense_variant	38/43	5		ENSP00000488964

Frequencies

GnomAD3 genomes

AF:

0.00788

AC:

1199

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00198

AC:

427

AN:

215524

Hom.:

AF XY:

0.00138

AC XY:

162

AN XY:

116976

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.00135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000184

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000314

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000874

AC:

1260

AN:

1441944

Hom.:

Cov.:

AF XY:

0.000727

AC XY:

520

AN XY:

715558

show subpopulations

Gnomad4 AFR exome

AF:

0.0302

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000204

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000263

Gnomad4 OTH exome

AF:

0.00223

GnomAD4 genome

AF:

0.00786

AC:

1197

AN:

152334

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0273

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00934

ESP6500AA

AF:

0.0290

AC:

127

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00220

AC:

264

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.80

N;.

REVEL

Benign

0.081

Sift

Benign

0.25

T;.

Sift4G

Benign

0.33

T;T

Polyphen

0.10

B;.

Vest4

0.17

MVP

0.36

ClinPred

0.011

GERP RS

-1.4

Varity_R

0.080

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over