chr17-82081851-G-C

Variant names:

• chr17-82081851-G-C
• rs76966965
• NM_004104.5:c.6164-8C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004104.5(FASN):​c.6164-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,599,194 control chromosomes in the GnomAD database, including 241 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (118 hom., cov: 30)
  • Exomes 𝑓: 0.0023 (123 hom.)
• Consequence: FASN NM_004104.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001393
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.01
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-82081851-G-C is Benign according to our data. Variant chr17-82081851-G-C is described in ClinVar as Benign. ClinVar VariationId is 462092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.6164-8C>G		splice_region intron	N/A	NP_004095.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.6164-8C>G		splice_region intron	N/A	ENSP00000304592.2
	FASN	ENST00000634990.1	TSL:5	c.6158-8C>G		splice_region intron	N/A	ENSP00000488964.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3284 AN: 150916 Hom.: 115 Cov.: 30

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.0121

GnomAD2 exomes AF: 0.00553 AC: 1265 AN: 228900 AF XY: 0.00425

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000684

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00231 AC: 3340 AN: 1448158 Hom.: 123 Cov.: 42 AF XY: 0.00201 AC XY: 1444 AN XY: 719894

African (AFR) AF: 0.0835 AC: 2783 AN: 33346

American (AMR) AF: 0.00397 AC: 176 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45778

Middle Eastern (MID) AF: 0.00226 AC: 12 AN: 5318

European-Non Finnish (NFE) AF: 0.0000379 AC: 42 AN: 1108144

Other (OTH) AF: 0.00522 AC: 313 AN: 59952

GnomAD4 genome AF: 0.0219 AC: 3309 AN: 151036 Hom.: 118 Cov.: 30 AF XY: 0.0213 AC XY: 1575 AN XY: 73780

African (AFR) AF: 0.0767 AC: 3155 AN: 41110

American (AMR) AF: 0.00758 AC: 115 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67736

Other (OTH) AF: 0.0120 AC: 25 AN: 2082

Alfa AF: 0.00156 Hom.: 2

Bravo AF: 0.0255

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASN-related disorder Benign:1

Sep 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Epileptic encephalopathy Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.016
DANN	Benign	0.43
PhyloP100		-2.0
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs76966965; hg19: chr17-80039727;