Genetic Variant FASN:c.894+8C>A (chr17-82092689-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004104.5(FASN):c.894+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 821,134 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 10 hom. )

Consequence

FASN
NM_004104.5 splice_region, intron

Scores

Splicing: ADA: 0.00002170

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.740

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-82092689-G-T is Benign according to our data. Variant chr17-82092689-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 531098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASN	NM_004104.5 link	c.894+8C>A		splice_region_variant, intron_variant	Intron 7 of 42	ENST00000306749.4	NP_004095.4	P49327
FASN	XM_011523538.3 link	c.894+8C>A		splice_region_variant, intron_variant	Intron 7 of 42		XP_011521840.1	P49327

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASN	ENST00000306749.4 link	c.894+8C>A		splice_region_variant, intron_variant	Intron 7 of 42	1	NM_004104.5	ENSP00000304592.2		P49327
FASN	ENST00000634990.1 link	c.894+8C>A		splice_region_variant, intron_variant	Intron 7 of 42	5		ENSP00000488964.1		A0A0U1RQF0

Frequencies

GnomAD3 genomes

AF:

0.000878

AC:

118

AN:

134422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000136

Gnomad AMI

AF:

0.00123

Gnomad AMR

AF:

0.00154

Gnomad ASJ

AF:

0.00253

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00362

Gnomad FIN

AF:

0.00138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000927

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00123

AC:

228

AN:

185326

Hom.:

AF XY:

0.00140

AC XY:

142

AN XY:

101356

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000453

Gnomad ASJ exome

AF:

0.00259

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00409

Gnomad FIN exome

AF:

0.00108

Gnomad NFE exome

AF:

0.000801

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.00169

AC:

1159

AN:

686620

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

647

AN XY:

362002

show subpopulations

Gnomad4 AFR exome

AF:

0.000168

Gnomad4 AMR exome

AF:

0.000516

Gnomad4 ASJ exome

AF:

0.00389

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.00396

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.000877

AC:

118

AN:

134514

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

64758

show subpopulations

Gnomad4 AFR

AF:

0.000136

Gnomad4 AMR

AF:

0.00154

Gnomad4 ASJ

AF:

0.00253

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00363

Gnomad4 FIN

AF:

0.00138

Gnomad4 NFE

AF:

0.000927

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000657

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FASN: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epileptic encephalopathy

Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.16

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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

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